Peptides for the treatment of hearing

ABSTRACT

Peptides for the treatment of inflammation, and therapeutic uses and methods of using the same are disclosed. Peptides including a transducing sequence are effective for inhibiting cytokine activity and TNF-α secretion through interaction with toll-like receptor signaling pathways. Experiments are described illustrating the efficacy of the compounds in treating otitis media, noise-induced hearing loss, age-related hearing loss, and improvement of ordinary hearing.

CROSS REFERENCE

This application claims priority from U.S. Provisional Application No.61/472,301, filed on Apr. 6, 2011; U.S. Provisional Application No.61/472,300, filed on Apr. 6, 2011; U.S. Provisional Application No.61/472,307, filed on Apr. 6, 2011; U.S. Provisional Application No.61/472,306, filed on Apr. 6, 2011; U.S. Provisional Application No.61/472,311, filed on Apr. 6, 2011; and U.S. Provisional Application No.61/472,309, filed on Apr. 6, 2011, each of which is incorporated byreference herein in its entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

The invention was made with the support of the United States governmentunder Small Business innovation Research Contract number 5R44DC005882-05by the U.S. Small Business Administration.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. The ASCII copy, created on Apr. 4, 2012, isnamed 37501201.txt and is 122,035 bytes in size.

BACKGROUND OF THE INVENTION

Toll-like receptors (TLRs) recognize and respond to conserved motifstermed “pathogen-associated molecular patterns” (PAMPs). TLRs arecharacterized by an extracellular leucine-rich repeat motif and anintracellular Toll/IL-1 receptor (TIR) domain. Triggering of TLRs byPAMPs initiates a series of intracellular signaling events resulting inan inflammatory immune response designed to contain and eliminate thepathogen. Viruses encode immunoregulatory proteins, such as A52R(produced by the vaccina virus), that can effectively inhibitintracellular TIR signaling resulting in a diminished inflammatoryimmune response.

Noise induced hearing loss is the second most common cause of hearingloss. Noise can damage the hair cells in the inner ear and can causehearing loss, ear ringing and distortion of sounds. Similarly, tissuedamage related to aging can cause or exacerbate hearing loss in animals.

SUMMARY OF THE INVENTION

A method of treating noise-induced hearing loss, or treating age-relatedhearing loss, or improving hearing, the method comprising administeringto a subject in need or want of any of the foregoing atherapeutically-effective amount of a peptide that is:

a) a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

-   -   each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl        group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an        aminocarbonyl group, or both cap^(N) groups together with N form        a heterocycle;    -   tran^(N) and tran^(C) are each independently a transducing        sequence or absent;    -   pep^(N) and pep^(C) are each independently an amino acid        sequence or absent;    -   X¹ is A, K, an acidic amino acid residue, or is absent;    -   X² is A, I, L, or V;    -   X³ is A, D, I, L, P, or V;    -   X⁴ is A, E, I, Y, or a basic amino acid residue;    -   X⁵ is A, I, L, or V;    -   X⁶ is A, G, S, T, or Y;    -   X⁷ is A, E, I, L, or V;    -   X⁸ is A, P, S, T, or an aromatic amino acid residue;    -   X⁹ is A, K, or an acidic amino acid residue;    -   X¹⁰ is A, C, M, S, α-aminobutyric acid, or norvaline;    -   X¹¹ is A, I, L, V, or is absent;    -   X¹² is G or is absent;    -   x is 1, 2, or 3;    -   cap^(C) is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino,        dialkylamino, or a heterocycle; and    -   each amino acid residue side chain is independently optionally        capped with a capping group; or

b) a peptide comprising: IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227);LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287);RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO: 305), wherein each terminusand each amino acid residue side chain of the peptide is independentlyoptionally capped with a capping group, and wherein the peptideoptionally further comprises a transducing sequence positioned at theC-terminus of the peptide,

or a stereoisomer or pharmaceutically-acceptable salt of any of theforegoing peptides.

DESCRIPTION OF THE FIGURES

FIG. 1: Illustrates an assay for crossing the tympanic membrane byFITC-labeled P13. FIG. 1A. Bright field microscopy demonstrates cells inmiddle ear fluid. FIG. 1B. Fluorescent microscopy demonstratesFITC-labeled P13 associated with cells in middle ear fluid.

FIG. 2: P13 (SEQ ID NO: 369) reduces middle ear inflammation. BALB/cmice (n=6 in PBS group and n=7 in P13 (SEQ ID NO: 369) group) wereinjected with heat-killed S. pneumonia, treated 24 hours later withtopical (ear drop) administration of P13 (SEQ ID NO: 369) (1 μg), andhistology was examined 72 hours after bacteria introduction. Panel A:cell number within middle ear; Panel B: fluid area within middle ear.Note: Animal with high cell number and high fluid area in the P13 (SEQID NO: 369) treated group is the same animal.

FIG. 3: Topical administration of P13 (SEQ ID NO: 369) significantlyimproves hearing thresholds. BALB/c mice were administered heat-killedS. pneumonia, 24 hours later mice were treated topically (ear drops)with P13 (SEQ ID NO: 369) (1 μg) or PBS. Panel A: Hearing thresholds at4, 8, 16 and 32 kHz were quantified by ABR at days 5 and 13 days afteradministration of bacteria. Hearing loss was calculated by subtractingthe background ABR from post-treatment ABR and summing acrossfrequencies. Panel B: Number of animals with >20 DB hearing loss acrossall frequencies. Number of animals is in parentheses.

FIG. 4: Percent Inhibition of TNF-α secretion by peptides T52 (SEQ IDNO: 368), S5 (SEQ ID NO: 255) and P13 (SEQ ID NO: 369). RAW264.7 cellswere plated at 3×10⁵ cells/well in 48-well plates. After 24 h the cellswere incubated with peptide at various concentrations at roomtemperature in triplicate for 15 minutes and then stimulated with 1μg/mL CpG-ODN. Cells were then incubated for 4 hours at 37° C.,supernatants collected, and TNF-α measured by ELISA. Percent inhibitionwas calculated by comparing TNF-α secretion from cells incubated withpeptide to control cells with no peptide treatment.

FIG. 5: Illustrates the affect of P13 (SEQ ID NO: 369) and a controlpeptide on noise-induced hearing loss.

FIG. 6: Illustrates the inhibition of TNF-α production in necrotic cellextract-stimulated cells by P13 (SEQ ID NO: 369) and P7 (SEQ ID NO:379).

FIG. 7: Illustrates the affect of P13 (SEQ ID NO: 369) on age-relatedhearing loss in C57Bl/6 mice.

FIG. 8: Illustrates the improvement of ordinary hearing in BALB/c miceupon treatment with P13 (SEQ ID NO: 369).

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are incorporated by reference herein to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

The treatment and control of natural and pathogen-induced inflammationrepresents a significant clinical challenge. The targeting of theTLR/TIR signaling cascade represents one approach to controlinflammation; thus the identification of peptides derived from the A52Rprotein or A52R-like proteins finds therapeutic applications. Thepeptides and pharmaceutical compositions of the invention disclosedherein, and uses and methods of using the same, present a solution tothe problem of controlling inflammation, regulating cellular pathwaysassociated with inflammation, ameliorating noise-induced and age-relatedhearing loss, and improving normal hearing. Peptides described hereincan be useful for treating, preventing, or both treating and preventingthe conditions described herein.

Throughout the disclosure, amino acid residues of the peptides of theinvention are referenced by one or both of the standard abbreviationsknown in the art: a) single-letter abbreviations, such as R forarginine, D for aspartic acid, V for valine, etc.; and b) three-letterabbreviations, such as Arg for arginine, Asp for aspartic acid, Val forvaline, etc. The invention contemplates both L- and D-forms of aminoacid residues. In cases wherein the abbreviation refers only to an aminoacid residue of the D-configuration, the abbreviation is preceded by theterm, “D-,” for example, D-Arg for D-arginine, D-Asp for D-asparticacid, D-Val for D-valine, etc.

Toll-Like Receptor Signaling

Toll-Like receptors (“TLRs”) are conserved molecular receptors thatrecognize structures from bacteria, fungi, protozoa, and viruses.Activation of TLRs initiates a series of intracellular events resultingin an innate immune response characterized by the production ofpro-inflammatory cytokines (References 2-9). TLR signaling originatesfrom the cytoplasmic Toll/interleukin-1 receptor (TIR) domain, conservedamong all TLRs. Not limited by any theory, in certain embodiments,adapter molecule MyD88, containing both a TIR domain and a death domain,can associate with the TIR domain of TLRs and IRAK proteins.Phosporylation of IRAK can then lead to association with TRAF6 andsubsequent activation of NF-κB and secretion of pro-inflammatorycytokines (References 14, 22-25).

Peptides

Vaccinia virus, a member of the poxvirus family, is a DNA virus that hasbeen demonstrated to encode immunomodulatory proteins (References15-18). One of these proteins, A52R, has been shown to inhibit NF-κBactivation following initiation of the TIR signaling cascade (References15 and 18). Recent studies have demonstrated that A52R inhibits TRsignaling and contributes to the virulence of vaccinia virus. In certainembodiments, cell activation in response to different PAMPs involves anumber of intracellular molecules common to all TLRs, including but notlimited to MyD88, members of the IL-1 receptor-associated kinase (IRAK)proteins, TNF receptor associated factor (TRAF6), and NF-κB (Reference1).

Harte and colleagues (Reference 18) have demonstrated that the A52Rprotein inhibits TIR signaling by binding to both IRAK2 and TRAF6.Deletion of the A52R protein from vaccinia virus results in reducedviral virulence.

The peptide 13 (“P13”) sequence (DIVKLTVYDCI (SEQ ID NO: 369)) wasderived from the A52R sequence from vaccinia virus. Blast searchanalysis shows that peptide P13 (SEQ ID NO: 369) has 100% homology withsequences found within larger proteins from vaccinia virus other thanA52R, two proteins from cowpox virus, and one protein from rabbit poxvirus. Peptide 13 (SEQ ID NO: 369) was shown to have significanthomology with three separate proteins from different strains of variola(smallpox) virus: i) A46L from variola major virus strain India; ii)A49L from variola minor virus Garcia; and iii) A44L from variola majorvirus strain.

P13 (SEQ ID NO: 369) inhibits toll-like receptor-dependent signaling(U.S. Pat. No. 7,192,930 and US2008/0039395 incorporated herein byreference in their entirety). In some embodiments, structure-activitytesting can be performed to identify amino acid residues in the P13 (SEQID NO: 369) sequence that can be substituted for enhanced activity.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a peptide derived from A52R. In some embodiments,the pharmaceutical composition is an aural pharmaceutical composition.

In some embodiments, the peptide is P13 (SEQ ID NO: 369). In someembodiments, the peptide is derived from P13 (SEQ ID NO: 369). In someembodiments, the peptide is a P13 (SEQ ID NO: 369) variant, derivative,stereoisomer, or analogue. In some embodiments, the peptide comprisesthe amino acid sequence LEEYFMY (SEQ ID NO: 370). In some embodiments,the peptide comprises the amino acid sequence FTILEEYFMY (SEQ ID NO:371). In some embodiments, the peptide comprises the amino acid sequenceDIVKLTVYDCI (SEQ ID NO: 369). In some embodiments, the peptide comprisesthe amino acid sequence VYDCI (SEQ ID NO: 372). In some embodiments, thepeptide comprises the amino acid sequence VYACI (SEQ ID NO: 373). Insome embodiments, the peptide comprises the amino acid sequence KLTVY(SEQ ID NO: 374). In some embodiments, the peptide comprises the aminoacid sequence KLYVY (SEQ ID NO: 375). In some embodiments, the peptidecomprises the amino acid sequence KVYVY (SEQ ID NO: 376). In someembodiments, the peptide comprises 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or50 residues. In some embodiments, the peptide comprises from about 4 toabout 50 residues. In some embodiments, the peptide comprises from 4-50residues.

In some embodiments, a peptide comprises a transducing sequence. Thetransducing sequence can participate in cellular uptake. The presence ofthe transducing sequence can lead to enhanced or selective cellularuptake. In some embodiments, the transducing sequence is at theN-terminus of the peptide. In some embodiments, the transducing sequenceis at the C-terminus of the peptide.

A non-limiting example of a transducing sequence is a poly-argininesequence. In some embodiments, the poly-arginine sequence comprisesarginine residues. In some embodiments, the poly-arginine sequenceconsists of arginine residues. In some embodiments, the transducingsequence comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 or 20 arginine residues. In some embodiments, the transducingsequence comprises nine arginine residues. In some embodiments, thetransducing sequence comprises nine arginine residues. In someembodiments, the transducing sequence consists of about nine arginineresidues. In some embodiments, the transducing sequence consists of ninearginine residues. The arginine residues of the transducing sequence canbe L-arginine, D-arginine, or a mixture of L- and D-arginine in anyproportion.

Table 1 provides non-limiting examples of peptides of the invention.Exemplary peptides SEQ ID NOS 187-316 are those derived from A52R. Ofpeptides SEQ ID NOs 187-316, a subset is further designated S1-S22 (SEQID NOs: 228-230; 254-263; 265-267; 269; and 288-292). Other examplesinclude peptides derived from P13 (SEQ ID NO: 369) (“T peptides”). Insome embodiments, the present invention provides a pharmaceuticalcomposition comprising a peptide comprising any amino acid sequencelisted in Table 1. In some embodiments, the present invention provides apharmaceutical composition comprising any peptide listed in Table 1. Insome embodiments, the present invention provides a pharmaceuticalcomposition comprising a peptide comprising any amino acid sequence ofS1-S22 (SEQ ID NOs: 228-230; 254-263; 265-267; 269; and 288-292). Insome embodiments, the present invention provides a pharmaceuticalcomposition comprising any peptide of S1-S22 (SEQ ID NOs: 228-230;254-263; 265-267; 269; and 288-292). In some embodiments, the presentinvention provides a pharmaceutical composition comprising a peptidecomprising any amino acid sequence of T1-T56 (SEQ ID NOs: 183-186; and317-368). In some embodiments, the present invention provides apharmaceutical composition comprising any peptide of T1-T56 (SEQ ID NOs:183-186; and 317-368). In some embodiments, the peptide has atransducing sequence. In some embodiments, the transducing sequence ispoly-arginine. In some embodiments, the peptide comprises the sequenceof any one of SEQ ID NOS: 42-44, 68-77, 79-81, 83, 102-106, 133, 141,151, 166, 167, 181, 182, 228-230, 254-263, 265-267, 269, 288-292, 319,327, 337, 352, 353, 367, and 368. In some embodiments, the peptidecomprises the sequence of T3 (SEQ ID NO: 319), T11 (SEQ ID NO: 327), T21(SEQ ID NO: 337), T36 (SEQ ID NO: 352), T37 (SEQ ID NO: 353), T51 (SEQID NO: 367), or T52 (SEQ ID NO: 368). In some embodiments, the peptidecomprises the sequence of T3-R⁹ (SEQ ID NO: 133), T11-R⁹ (SEQ ID NO:141), T21-R⁹ (SEQ ID NO: 151), T36-R⁹ (SEQ ID NO: 166), T37-R⁹ (SEQ IDNO: 167), T51-R⁹ (SEQ ID NO: 181), or T52-R⁹ (SEQ ID NO: 182). In someembodiments, a peptide of the invention has a sequence comprising anyone of SEQ ID NOS: 1-369 and 378-396. In some embodiments, a peptide ofthe invention has a sequence comprising any amino acid sequencecontemplated herein. Any of the forgoing peptides and pharmaceuticalcompositions thereof can be used for the treatment of a condition, forexample, noise-induced hearing loss or age-related hearing loss. Thesame peptides can also be used for the improvement of normal hearing.

TABLE 1 Exemplary peptides of the invention Peptide Sequence 1-R⁹YIKVQKQDIVKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 1) 2-R⁹IKVQKQDIVKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 2) 3-R⁹KVQKQDIVKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 3) 4-R⁹VQKQDIVKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 4) 5-R⁹QKQDIVKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 5) 6-R⁹KQDIVKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 6) 7-R⁹QDIVKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 7) 8-R⁹DIVKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 8) 9-R⁹IVKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 9) 10-R⁹VKLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 10) ll-R⁹KLTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 11) 12-R⁹LTVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 12) 13-R⁹TVYDCISMIGLCARRRRRRRRR (SEQ ID NO: 13) 14-R⁹VYDCISMIGLCARRRRRRRRR (SEQ ID NO: 14) 15-R⁹YDCISMIGLCARRRRRRRRR (SEQ ID NO: 15) 16-R⁹DCISMIGLCARRRRRRRRR (SEQ ID NO: 16) 17-R⁹CISMIGLCARRRRRRRRR (SEQ ID NO: 17) 18-R⁹ISMIGLCARRRRRRRRR (SEQ ID NO: 18) 19-R⁹ SMIGLCARRRRRRRRR (SEQ ID NO: 19)20-R⁹ MIGLCARRRRRRRRR (SEQ ID NO: 20) 21-R⁹IGLCARRRRRRRRR (SEQ ID NO: 21) 22-R⁹YIKVQKQDIVKLTVYDCISMIGLCRRRRRRRRR (SEQ ID NO: 22) 23-R⁹YIKVQKQDIVKLTVYDCISMIGLRRRRRRRRR (SEQ ID NO: 23) 24-R⁹YIKVQKQDIVKLTVYDCISMIGRRRRRRRRR (SEQ ID NO: 24) 25-R⁹YIKVQKQDIVKLTVYDCISMIRRRRRRRRR (SEQ ID NO: 25) 26-R⁹YIKVQKQDIVKLTVYDCISMRRRRRRRRR (SEQ ID NO: 26) 27-R⁹YIKVQKQDIVKLTVYDCISRRRRRRRRR (SEQ ID NO: 27) 28-R⁹YIKVQKQDIVKLTVYDCIRRRRRRRRR (SEQ ID NO: 28) 29-R9YIKVQKQDIVKLTVYDCRRRRRRRRR (SEQ ID NO: 29) 30-R⁹YIKVQKQDIVKLTVYDRRRRRRRRR (SEQ ID NO: 30) 31-R⁹YIKVQKQDIVKLTVYRRRRRRRRR (SEQ ID NO: 31) 32-R⁹YIKVQKQDIVKLTVRRRRRRRRR (SEQ ID NO: 32) 33-R⁹YIKVQKQDIVKLTRRRRRRRRR (SEQ ID NO: 33) 34-R⁹YIKVQKQDIVKLRRRRRRRRR (SEQ ID NO: 34) 35-R⁹YIKVQKQDIVKRRRRRRRRR (SEQ ID NO: 35) 36-R⁹YIKVQKQDIVRRRRRRRRR (SEQ ID NO: 36) 37-R⁹YIKVQKQDIRRRRRRRRR (SEQ ID NO: 37) 38-R⁹YIKVQKQDRRRRRRRRR (SEQ ID NO: 38) 39-R⁹ YIKVQKQRRRRRRRRR (SEQ ID NO: 39)40-R⁹ YIKVQKRRRRRRRRR (SEQ ID NO: 40) 41-R⁹YIKVQRRRRRRRRR (SEQ ID NO: 41) 42 (S1)-R⁹EMFTILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 42) 43 (S2)-R⁹MFTILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 43) 44 (S3)-R⁹FTILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 44) 45-R⁹TILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 45) 46-R⁹ILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 46) 47-R⁹LEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 47) 48-R⁹EEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 48) 49-R⁹EYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 49) 50-R⁹YFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 50) 51-R⁹FMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 51) 52-R⁹MYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 52) 53-R⁹YRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 53) 54-R⁹RGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 54) 55-R⁹GLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 55) 56-R⁹LLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 56) 57-R⁹LGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 57) 58-R⁹GLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 58) 59-R⁹LRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 59) 60-R⁹RIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 60) 61-R⁹IKYGRLFNEIRRRRRRRRR (SEQ ID NO: 61) 62-R⁹KYGRLFNEIRRRRRRRRR (SEQ ID NO: 62) 63-R⁹YGRLFNEIRRRRRRRRR (SEQ ID NO: 63) 64-R⁹ GRLFNEIRRRRRRRRR (SEQ ID NO: 64)65-R⁹ RLFNEIRRRRRRRRR (SEQ ID NO: 65) 66-R⁹LFNEIRRRRRRRRR (SEQ ID NO: 66) 67-R⁹EMFTILEEYFMYRGLLGLRIKYGRLFNERRRRRRRRR (SEQ ID NO: 67) 68 (S4)-R⁹EMFTILEEYFMYRGLLGLRIKYGRLFNRRRRRRRRR (SEQ ID NO: 68) 69 (S5)-R⁹EMFTILEEYFMYRGLLGLRIKYGRLFRRRRRRRRR (SEQ ID NO: 69) 70 (S6)-R⁹EMFTILEEYFMYRGLLGLRIKYGRLRRRRRRRRR (SEQ ID NO: 70) 71 (S7)-R⁹EMFTILEEYFMYRGLLGLRIKYGRRRRRRRRRR (SEQ ID NO: 71) 72 (S8)-R⁹EMFTILEEYFMYRGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 72) 73 (S9)-R⁹EMFTILEEYFMYRGLLGLRIKYRRRRRRRRR (SEQ ID NO: 73) 74 (S10)-R⁹EMFTILEEYFMYRGLLGLRIKRRRRRRRRR (SEQ ID NO: 74) 75 (S11)-R⁹EMFTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 75) 76 (S12)-R⁹EMFTILEEYFMYRGLLGLRRRRRRRRRR (SEQ ID NO: 76) 77 (S13)-R⁹EMFTILEEYFMYRGLLGLRRRRRRRRR (SEQ ID NO: 77) 78-R⁹EMFTILEEYFMYRGLLGRRRRRRRRR (SEQ ID NO: 78) 79 (S14)-R⁹EMFTILEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 79) 80 (S15)-R⁹EMFTILEEYFMYRGLRRRRRRRRR (SEQ ID NO: 80) 81 (S16)-R⁹EMFTILEEYFMYRGRRRRRRRRR (SEQ ID NO: 81) 82-R⁹EMFTILEEYFMYRRRRRRRRRR (SEQ ID NO: 82) 83 (S17)-R⁹EMFTILEEYFMYRRRRRRRRR (SEQ ID NO: 83) 84-R⁹EMFTILEEYFMRRRRRRRRR (SEQ ID NO: 84) 85-R⁹EMFTILEEYFRRRRRRRRR (SEQ ID NO: 85) 86-R⁹EMFTILEEYRRRRRRRRR (SEQ ID NO: 86) 87-R⁹EMFTILEERRRRRRRRR (SEQ ID NO: 87) 88-R⁹ EMFTILERRRRRRRRR (SEQ ID NO: 88)89-R⁹ EMFTILRRRRRRRRR (SEQ ID NO: 89) 90-R⁹EMFTIRRRRRRRRR (SEQ ID NO: 90) 91-R⁹MFTILLEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 91) 92-R⁹FTILLEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 92) 93-R⁹TILLEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 93) 94-R⁹ILLEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 94) 95-R⁹LLEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 95) 96-R⁹LEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 96) 97-R⁹EYFMYRGLLRRRRRRRRR (SEQ ID NO: 97) 98-R⁹YFMYRGLLRRRRRRRRR (SEQ ID NO: 98) 99-R⁹ FMYRGLLRRRRRRRRR (SEQ ID NO: 99)100-R⁹ MYRGLLRRRRRRRRR (SEQ ID NO: 100) 101-R⁹YRGLLRRRRRRRRR(SEQ ID NO: 101) 102 (S18)-R⁹MFTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 102) 103 (S19)-R⁹FTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 103) 104 (S20)-R⁹TILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 104) 105 (S21)-R⁹ILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 105) 106 (S22)-R⁹LEEYFMYGLLGLRIRRRRRRRRR (SEQ ID NO: 106) 107-R⁹EYFMYRGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 107) 108-R⁹YFMYRGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 108) 109-R⁹FMYRGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 109) 110-R⁹MYRGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 110) 111-R⁹YRGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 111) 112-R⁹RGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 112) 113-R⁹GLLGLRIKYGRRRRRRRRR (SEQ ID NO: 113) 114-R⁹LLGLRIKYGRRRRRRRRR (SEQ ID NO: 114) 115-R⁹LGLRIKYGRRRRRRRRR (SEQ ID NO: 115) 116-R⁹GLRIKYGRRRRRRRRR (SEQ ID NO: 116) 117-R⁹LRIKYGRRRRRRRRR (SEQ ID NO: 117) 118-R⁹ RIKYGRRRRRRRRR (SEQ ID NO: 118)119-R⁹ EEYFMRRRRRRRRR (SEQ ID NO: 119) 120-R⁹EEYFMYRRRRRRRRR (SEQ ID NO: 120) 121-R⁹EEYFMYRRRRRRRRRR (SEQ ID NO: 121) 122-R⁹EEYFMYRGRRRRRRRRR (SEQ ID NO: 122) 123-R⁹EEYFMYRGLRRRRRRRRR (SEQ ID NO: 123) 124-R⁹EEYFMYRGLLRRRRRRRRR (SEQ ID NO: 124) 125-R⁹EEYFMYRGLLGRRRRRRRRR (SEQ ID NO: 125) 126-R⁹EEYFMYRGLLGLRRRRRRRRR (SEQ ID NO: 126) 127-R⁹EEYFMYRGLLGLRRRRRRRRRR (SEQ ID NO: 127) 128-R⁹EEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 128) 129-R⁹EEYFMYRGLLGLRIKRRRRRRRRR (SEQ ID NO: 129) 130-R⁹EEYFMYRGLLGLRIKYRRRRRRRRR (SEQ ID NO: 130) T1-R⁹IVKLTVYDCIRRRRRRRRR (SEQ ID NO: 131) T2-R⁹DIVKLTVYDCRRRRRRRRR (SEQ ID NO: 132) T3-R⁹AIVKLTVYDCIRRRRRRRRR (SEQ ID NO: 133) T4-R⁹DAVKLTVYDCIRRRRRRRRR (SEQ ID NO: 134) T5-R⁹DIAKLTVYDCIRRRRRRRRR (SEQ ID NO: 135) T6-R⁹DIVALTVYDCIRRRRRRRRR (SEQ ID NO: 136) T7-R⁹DIVKATVYDCIRRRRRRRRR (SEQ ID NO: 137) T8-R⁹DIVKLAVYDCIRRRRRRRRR (SEQ ID NO: 138) T9-R⁹DIVKLTAYDCIRRRRRRRRR (SEQ ID NO: 139) T10-R⁹DIVKLTVADCIRRRRRRRRR (SEQ ID NO: 140) T11-R⁹DIVKLTVYACIRRRRRRRRR (SEQ ID NO: 141) T12-R⁹DIVKLTVYDAIRRRRRRRRR (SEQ ID NO: 142) T13-R⁹DIVKLTVYDCARRRRRRRRR (SEQ ID NO: 143) T14-R⁹EIVKLTVYDCIRRRRRRRRR (SEQ ID NO: 144) T15-R⁹DIVKLTVYECIRRRRRRRRR (SEQ ID NO: 145) T16-R⁹DIVRLTVYDCIRRRRRRRRR (SEQ ID NO: 146) T17-R⁹DIVHLTVYDCIRRRRRRRRR (SEQ ID NO: 147) T18-R⁹KIVKLTVYKCIRRRRRRRRR (SEQ ID NO: 148) T19-R⁹DIVELTVYDCIRRRRRRRRR (SEQ ID NO: 149) T20-R⁹DIVKLSVYDCIRRRRRRRRR (SEQ ID NO: 150) T21-R⁹DIVKLYVYDCIRRRRRRRRR (SEQ ID NO: 151) T22-R⁹DIVKLTVSDCIRRRRRRRRR (SEQ ID NO: 152) T23-R⁹DIVKLTVTDCIRRRRRRRRR (SEQ ID NO: 153) T24-R⁹DIVKLTVWDCIRRRRRRRRR (SEQ ID NO: 154) T25-R⁹DIVKLTVFDCIRRRRRRRRR (SEQ ID NO: 155) T26-R⁹DIVKLTVYDMIRRRRRRRRR (SEQ ID NO: 156) T27-R⁹DIVKLTVYDSIRRRRRRRRR (SEQ ID NO: 157) T28-R⁹DIVKLTVYDXaaIRRRRRRRRR (SEQ ID NO: 158) T29-R⁹DIVKLTVYDXaaIRRRRRRRRR (SEQ ID NO: 159) T30-R⁹DIVKLTVYDXaaIRRRRRRRRR (SEQ ID NO: 160) T31-R⁹DIVKLTVYDXaaIRRRRRRRRR (SEQ ID NO: 161) T32-R⁹DIVKLTVYDXaaIRRRRRRRRR (SEQ ID NO: 162) T33-R⁹DLVKLTVYDCIRRRRRRRRR (SEQ ID NO: 163) T34-R⁹DVVKLTVYDCIRRRRRRRRR (SEQ ID NO: 164) T35-R⁹DILKLTVYDCIRRRRRRRRR (SEQ ID NO: 165) T36-R9DIIKLTVYDCIRRRRRRRRR (SEQ ID NO: 166) T37-R⁹DIVKVTVYDCIRRRRRRRRR (SEQ ID NO: 167) T38-R⁹DIVKITVYDCIRRRRRRRRR (SEQ ID NO: 168) T39-R⁹DIVKLTLYDCIRRRRRRRRR (SEQ ID NO: 169) T40-R⁹DIVKLTIYDCIRRRRRRRRR (SEQ ID NO: 170) T41-R⁹DIVKLTVYDCLRRRRRRRRR (SEQ ID NO: 171) T42-R⁹DIVKLTVYDCVRRRRRRRRR (SEQ ID NO: 172) T43-R⁹DIDKLTEYDSIRRRRRRRRR (SEQ ID NO: 173) T44-R⁹DIPKLGVPDCIRRRRRRRRR (SEQ ID NO: 174) T45-R⁹ICDYVTLKVIDRRRRRRRRR (SEQ ID NO: 175) T46-R⁹VDLVIDCIYKTRRRRRRRRR (SEQ ID NO: 176) T47-R⁹DIVKLTVYDCIDIVKLTVYDCIRRRRRRRRR (SEQ ID NO: 177) T48-R⁹IVKLTVYDCIRRRRRRRRR (N-succinyl) (SEQ ID NO: 178) T49-R⁹DIVKLTVYDCIGRRRRRRRRR (SEQ ID NO: 179) T50-R⁹DIVKLTVYDCIRRRRRRRRR (N-acetyl) (SEQ ID NO: 180) T51-R⁹AIVKLTVYACIRRRRRRRRR (SEQ ID NO: 181) T52-R⁹AIIKVYVYACIRRRRRRRRR (SEQ ID NO: 182) T53D-Asp-D-Ile-D-Val-D-Lys-D-Leu-D-Thr-D-Val-D-Tyr-D-Asp-D-Cys-D-Ile-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg (SEQ ID NO: 183) T54D-Asp-D-Ile-D-Val-D-Lys-D-Leu-D-Thr-D-Val-D-Tyr-D-Asp-D-Cys-D-Ile-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg (SEQ ID NO: 184)T55 D-Asp-D-Ile-D-Val-D-Lys-D-Leu-D-Thr-D-Val-D-Tyr-D-Asp-D-Cys-D-Ile(SEQ ID NO: 185) T56Asp-Ile-Val-Lys-Leu-Thr-Val-Tyr-Asp-Cys-Ile-D-Arg-D-Arg-D-Arg-D-Arg- D-Arg- D-Arg- D-Arg- D-Arg- D-Arg (SEQ ID NO: 186)   1YIKVQKQDIVKLTVYDCISMIGLCA (SEQ ID NO: 187)   2IKVQKQDIVKLTVYDCISMIGLCA (SEQ ID NO: 188)   3KVQKQDIVKLTVYDCISMIGLCA (SEQ ID NO: 189)   4VQKQDIVKLTVYDCISMIGLCA (SEQ ID NO: 190)   5QKQDIVKLTVYDCISMIGLCA (SEQ ID NO: 191)   6KQDIVKLTVYDCISMIGLCA (SEQ ID NO: 192)   7QDIVKLTVYDCISMIGLCA (SEQ ID NO: 193)   8DIVKLTVYDCISMIGLCA (SEQ ID NO: 194)   9IVKLTVYDCISMIGLCA (SEQ ID NO: 195)  10 VKLTVYDCISMIGLCA (SEQ ID NO: 196) 11 KLTVYDCISMIGLCA (SEQ ID NO: 197)  12 LTVYDCISMIGLCA (SEQ ID NO: 198) 13 TVYDCISMIGLCA (SEQ ID NO: 199)  14 VYDCISMIGLCA (SEQ ID NO: 200)  15YDCISMIGLCA (SEQ ID NO: 201)  16 DCISMIGLCA (SEQ ID NO: 202)  17CISMIGLCA (SEQ ID NO: 203)  18 ISMIGLCA (SEQ ID NO: 204)  19SMIGLCA (SEQ ID NO: 205)  20 MIGLCA (SEQ ID NO: 206)  21IGLCA (SEQ ID NO: 207)  22 YIKVQKQDIVKLTVYDCISMIGLC (SEQ ID NO: 208)  23YIKVQKQDIVKLTVYDCISMIGL (SEQ ID NO: 209)  24YIKVQKQDIVKLTVYDCISMIG (SEQ ID NO: 210)  25YIKVQKQDIVKLTVYDCISMI (SEQ ID NO: 211)  26YIKVQKQDIVKLTVYDCISM (SEQ ID NO: 212)  27YIKVQKQDIVKLTVYDCIS (SEQ ID NO: 213)  28YIKVQKQDIVKLTVYDCI (SEQ ID NO: 214)  29YIKVQKQDIVKLTVYDC (SEQ ID NO: 215)  30 YIKVQKQDIVKLTVYD (SEQ ID NO: 216) 31 YIKVQKQDIVKLTVY (SEQ ID NO: 217)  32 YIKVQKQDIVKLTV (SEQ ID NO: 218) 33 YIKVQKQDIVKLT (SEQ ID NO: 219)  34 YIKVQKQDIVKL (SEQ ID NO: 220)  35YIKVQKQDIVK (SEQ ID NO: 221)  36 YIKVQKQDIV (SEQ ID NO: 222)  37YIKVQKQDI (SEQ ID NO: 223)  38 YIKVQKQD (SEQ ID NO: 224)  39YIKVQKQ (SEQ ID NO: 225)  40 YIKVQK (SEQ ID NO: 226)  41YIKVQ (SEQ ID NO: 227)  42(S1)EMFTILEEYFMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 228)  43(S2)MFTILEEYFMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 229)  44(S3)FTILEEYFMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 230)  45TILEEYFMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 231)  46ILEEYFMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 232)  47LEEYFMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 233)  48EEYFMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 234)  49EYFMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 235)  50YFMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 236)  51FMYRGLLGLRIKYGRLFNEI (SEQ ID NO: 237)  52MYRGLLGLRIKYGRLFNEI (SEQ ID NO: 238)  53YRGLLGLRIKYGRLFNEI (SEQ ID NO: 239)  54RGLLGLRIKYGRLFNEI (SEQ ID NO: 240)  55 GLLGLRIKYGRLFNEI (SEQ ID NO: 241) 56 LLGLRIKYGRLFNEI (SEQ ID NO: 242)  57 LGLRIKYGRLFNEI (SEQ ID NO: 243) 58 GLRIKYGRLFNEI (SEQ ID NO: 244)  59 LRIKYGRLFNEI (SEQ ID NO: 245)  60RIKYGRLFNEI (SEQ ID NO: 246)  61 IKYGRLFNEI (SEQ ID NO: 247)  62KYGRLFNEI (SEQ ID NO: 248)  63 YGRLFNEI (SEQ ID NO: 249)  64GRLFNEI (SEQ ID NO: 250)  65 RLFNEI (SEQ ID NO: 251)  66LFNEI (SEQ ID NO: 252)  67 EMFTILEEYFMYRGLLGLRIKYGRLFNE (SEQ ID NO: 253) 68(S4) EMFTILEEYFMYRGLLGLRIKYGRLFN (SEQ ID NO: 254)  69(S5)EMFTILEEYFMYRGLLGLRIKYGRLF (SEQ ID NO: 255)  70(S6)EMFTILEEYFMYRGLLGLRIKYGRL (SEQ ID NO: 256)  71(S7)EMFTILEEYFMYRGLLGLRIKYGR (SEQ ID NO: 257)  72(S8)EMFTILEEYFMYRGLLGLRIKYG (SEQ ID NO: 258)  73(S9)EMFTILEEYFMYRGLLGLRIKY (SEQ ID NO: 259)  74(S10)EMFTILEEYFMYRGLLGLRIK (SEQ ID NO: 260)  75(S11)EMFTILEEYFMYRGLLGLRI (SEQ ID NO: 261)  76(S12)EMFTILEEYFMYRGLLGLR (SEQ ID NO: 262)  77(S13)EMFTILEEYFMYRGLLGL (SEQ ID NO: 263)  78EMFTILEEYFMYRGLLG (SEQ ID NO: 264)  79(S14)EMFTILEEYFMYRGLL (SEQ ID NO: 265)  80(S15)EMFTILEEYFMYRGL (SEQ ID NO: 266)  81(S16)EMFTILEEYFMYRG (SEQ ID NO: 267)  82 EMFTILEEYFMYR (SEQ ID NO: 268) 83(S17) EMFTILEEYFMY (SEQ ID NO: 269)  84 EMFTILEEYFM (SEQ ID NO: 270) 85 EMFTILEEYF (SEQ ID NO: 271)  86 EMFTILEEY (SEQ ID NO: 272)  87EMFTILEE (SEQ ID NO: 273)  88 EMFTILE (SEQ ID NO: 274)  89EMFTIL (SEQ ID NO: 275)  90 EMFTI (SEQ ID NO: 276)  91MFTILLEEYFMYRGLL (SEQ ID NO: 277)  92 FTILLEEYFMYRGLL (SEQ ID NO: 278) 93 TILLEEYFMYRGLL (SEQ ID NO: 279)  94 ILLEEYFMYRGLL (SEQ ID NO: 280) 95 LLEEYFMYRGLL (SEQ ID NO: 281)  96 LEEYFMYRGLL (SEQ ID NO: 282)  97EYFMYRGLL (SEQ ID NO: 283)  98 YFMYRGLL (SEQ ID NO: 284)  99FMYRGLL (SEQ ID NO: 285) 100 MYRGLL (SEQ ID NO: 286) 101YRGLL (SEQ ID NO: 287) 102(S18) MFTILEEYFMYRGLLGLRI (SEQ ID NO: 288)103(S19) FTILLEEYFMYRGLLGLRI (SEQ ID NO: 289) 104(S20)TILLEEYFMYRGLLGLRI (SEQ ID NO: 290) 105(S21)ILLEEYFMYRGLLGLRI (SEQ ID NO: 291) 106(S22)LLEEYFMYGLLGLRI (SEQ ID NO: 292) 107 EYFMYRGLLGLRIKYG (SEQ ID NO: 293)108 YFMYRGLLGLRIKYG (SEQ ID NO: 294) 109 FMYRGLLGLRIKYG (SEQ ID NO: 295)110 MYRGLLGLRIKYG (SEQ ID NO: 296) 111 YRGLLGLRIKYG (SEQ ID NO: 297) 112RGLLGLRIKYG (SEQ ID NO: 298) 113 GLLGLRIKYG (SEQ ID NO: 299) 114LLGLRIKYG (SEQ ID NO: 300) 115 LGLRIKYG (SEQ ID NO: 301) 116GLRIKYG (SEQ ID NO: 302) 117 LRIKYG (SEQ ID NO: 303) 118RIKYG (SEQ ID NO: 304) 119 EEYFM (SEQ ID NO: 305) 120EEYFMY (SEQ ID NO: 306) 121 EEYFMYR (SEQ ID NO: 307) 122EEYFMYRG (SEQ ID NO: 308) 123 EEYFMYRGL (SEQ ID NO: 309) 124EEYFMYRGLL (SEQ ID NO: 310) 125 EEYFMYRGLLG (SEQ ID NO: 311) 126EEYFMYRGLLGL (SEO ID NO: 312) 127 EEYFMYRGLLGLR (SEQ ID NO: 313) 128EEYFMYRGLLGLRI (SEQ ID NO: 314) 129 EEYFMYRGLLGLRIKY (SEQ ID NO: 315)130 EEYFMYRGLLGLRIKY (SEQ ID NO: 316) T1 IVKLTVYDCI (SEQ ID NO: 317) T2DIVKLTVYDC (SEQ ID NO: 318) T3 AIVKLTVYDCI (SEQ ID NO: 319) T4DAVKLTVYDCI (SEQ ID NO: 320) T5 DIAKLTVYDCI (SEQ ID NO: 321) T6DIVALTVYDCI (SEQ ID NO: 322) T7 DIVKATVYDCI (SEQ ID NO: 323) T8DIVKLAVYDCI (SEQ ID NO: 324) T9 DIVKLTAYDCI (SEQ ID NO: 325) T10DIVKLTVADCI (SEQ ID NO: 326) T11 DIVKLTVYACI (SEQ ID NO: 327) T12DIVKLTVYDAI (SEQ ID NO: 328) T13 DIVKLTVYDCA (SEQ ID NO: 329) T14EIVKLTVYDCI (SEQ ID NO: 330) T15 DIVKLTVYECI (SEQ ID NO: 331) T16DIVRLTVYDCI (SEQ ID NO: 332) T17 DIVHLTVYDCI (SEQ ID NO: 333) T18KIVKLTVYDCI (SEQ ID NO: 334) T19 DIVELTVYDCI (SEQ ID NO: 335) T20DIVKLSVYDCI (SEQ ID NO: 336) T21 DIVKLYVYDCI (SEQ ID NO: 337) T22DIVKLTVSDCI (SEQ ID NO: 338) T23 DIVKLTVTDCI (SEQ ID NO: 339) T24DIVKLTVWDCI (SEQ ID NO: 340) T25 DIVKLTVFDCI (SEQ ID NO: 341) T26DIVKLTVYDMI (SEQ ID NO: 342) T27 DIVKLTVYDSI (SEQ ID NO: 343) T28DIVKLTVYDXaaI (SEQ ID NO: 344) T29 DIVKLTVYDXaaI (SEQ ID NO: 345) T30DIVKLTVYDXaaI (SEQ ID NO: 346) T31 DIVKLTVYDXaaI (SEQ ID NO: 347) T32DIVKLTVYDXaaI (SEQ ID NO: 348) T33 DLVKLTVYDCI (SEQ ID NO: 349) T34DVVKLTVYDCI (SEQ ID NO: 350) T35 DILKLTVYDCI (SEQ ID NO: 351) T36DIIKLTVYDCI (SEQ ID NO: 352) T37 DIVKVTVYDCI (SEQ ID NO: 353) T38DIVKTIVYDCI (SEQ ID NO: 354) T39 DIVKLTLYDCI (SEQ ID NO: 355) T40DIVKLTIYDCI (SEQ ID NO: 356) T41 DIVKLTVYDCL (SEQ ID NO: 357) T42DIVKLTVYDCV (SEQ ID NO: 358) T43 DIDKLTEYDSI (SEQ ID NO: 359) T44DIPKLGVPDCI (SEQ ID NO: 360) T45 ICDYVTLKVID (SEQ ID NO: 361) T46VDLVIDCIYKT (SEQ ID NO: 362) T47 DIVKLTVYDCIDIVKLTVYDCI (SEQ ID NO: 363)T48 IVKLTVYDCI (N-succinyl) (SEQ ID NO: 364) T49DIVKLTVYDCIG (SEQ ID NO: 365) T50DIVKLTVYDCI (N-acetyl) (SEQ ID NO: 366) T51 AIVKLTVYACI (SEQ ID NO: 367)T52 AIIKVYVYACI (SEQ ID NO: 368) P13 DIVKLTVYDCI (SEQ ID NO: 369) P13-R⁹DIVKLTVYDCIRRRRRRRRR (SEQ ID NO: 378) P7EEYFMYRGLLGLRIKYG (SEQ ID NO: 379) P7-R⁹EEYFMYRGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 380) Z-1LEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 381) Z-2MFTILEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 382) Z-3FTILEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 383) Z-4TILEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 384) Z-5ILEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 385) Z-6FTILEEYFMYRGLLGLRI (SEQ ID NO: 386) Z-7TILEEYFMYRGLLGLRI (SEQ ID NO: 387) Z-8 ILEEYFMYRGLLGLRI (SEQ ID NO: 388)Z-9 LEEYFMYRGLLGLRI (SEQ ID NO: 389) Z-10MFTILEEYFMYRGLL (SEQ ID NO: 390) Z-11 FTILEEYFMYRGLL (SEQ ID NO: 391)Z-12 TILEEYFMYRGLL (SEQ ID NO: 392) Z-13 ILEEYFMYRGLL (SEQ ID NO: 393)Z-14 FTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 394) Z-15TILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 395) Z-16ILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 396) Legend to Table 1: Xaa inpeptide T28 (SEQ ID NO: 344) and T28-R⁹ (SEQ ID NO: 158) isL-Cysteine(S-carboxymethyl); Xaa in peptide T29 (SEQ ID NO: 345) andT29-R⁹ (SEQ ID NO: 159) is L-Cysteine(S-carbamidomethyl); Xaa in peptideT30 (SEQ ID NO: 346) and T30-R⁹ (SEQ ID NO: 160) is L-Cysteine(S-Acm);Xaa in peptide T31 (SEQ ID NO: 347) and T31-R⁹ (SEQ ID NO: 161) isa-Aminobutyric acid; and Xaa in peptide T32 (SEQ ID NO: 348) and T32-R⁹(SEQ ID NO: 162) is L-Norvaline.

Peptides of the invention and compositions comprising the same areeffective to modulate cellular activity. In some embodiments, modulatingcellular activity is accomplished by modulating cellular signaling.Activities can be regulated, for example, by a toll-like receptor. Insome embodiments, peptides and compositions of the invention inhibitcytokine secretion. In some embodiments, peptides and compositions ofthe invention enhance cytokine secretion. In some embodiments, cytokinesecretion is in response to toll-like receptor-dependent stimulation.

In some embodiments, administration of a peptide derived from A52R orP13 (SEQ ID NO: 369) can inhibit cytokine secretion by at least 10%,20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments,administration of a peptide derived from A52R or P13 (SEQ ID NO: 369)can enhance cytokine secretion by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%or 90%. In some embodiments the cytokine secretion is a result ofTLR-dependent signaling.

In some embodiments, the activity mediated by a toll-like receptor isTNF-α secretion. Peptides and compositions of the invention areeffective to provide 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%inhibition of TNF-α secretion following stimulation by LPS. Peptides andcompositions of the invention are effective to provide 10%, 20%, 30%,40%, 50%, 60%, 70%, 80% or 90% inhibition of TNF-α secretion followingstimulation by CpG-ODN. Peptides and compositions of the invention areeffective to provide 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%inhibition of TNF-α secretion following stimulation by LPS and/orCpG-ODN. Peptides and compositions of the invention are effective toprovide 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% enhancement ofTNF-α secretion following stimulation by LPS. Peptides and compositionsof the invention are effective to provide 10%, 20%, 30%, 40%, 50%, 60%,70%, 80% or 90% enhancement of TNF-α secretion following stimulation byCpG-ODN. Peptides and compositions of the invention are effective toprovide 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% enhancement ofTNF-α secretion following stimulation by LPS and/or CpG-ODN.

Some embodiments of the invention contemplate a peptide comprising theamino acid sequence DIVKLTVYDCI (SEQ ID NO: 369), linked to a 9-argininecell transduction sequence or other type of cell transduction sequence.The peptide DIVKLTVYDCIRRRRRRRRR (SEQ ID NO: 378) effectively inhibitedcytokine secretion in response to TLR activation. The peptide had noeffect on cytokine secretion resulting from cell activation that wasinitiated independent of TLR stimulation. Employing a mouse model ofotitis media with effusion (OME), administration of heat-inactivatedStreptococcus pneumoniae (S. pneumoniae) into the middle ears of BALB/cmice resulted in a significant inflammatory response that wasdramatically reduced with peptide treatment. Experiments have alsodemonstrated that the peptide will reduce pro-inflammatory mediators ina mouse model of LPS-induced septic shock. The peptide is effective inthe treatment of chronic inflammation initiated by bacterial or viralinfections.

In some embodiments, the invention contemplates a pharmaceuticalcomposition effective to:

a) decrease the amount of an middle ear fluid by about 30-80%;

b) decrease infiltrating cell number in middle ear fluid by about30-80%; and

c) decrease the thickness of a tympanic membrane by about 30-80% in amouse comprising inflammation of the ear, wherein the composition isadministered to the mouse in an amount of about 0.1 μg to 60 μg. In someembodiments, the pharmaceutical composition is an aural pharmaceuticalcomposition. In some embodiments, the pharmaceutical composition isformulated for intra-aural administration. In some embodiments, thepharmaceutical composition is formulated as a drop. In some embodiments,the pharmaceutical composition is formulated as an ear drop.

In some embodiments, a pharmaceutical composition of the inventioncomprises a peptide. In some embodiments, the peptide is P13 (SEQ ID NO:369) or a variant, derivative, stereoisomer, or analogue thereof. Insome embodiments, the peptide is P13 (SEQ ID NO: 369), a peptidecomprising P13 (SEQ ID NO: 369) and a poly-argenine domain, or a peptideof Table 1. In some embodiments, the peptide is P13 (SEQ ID NO: 369). Insome embodiments, the peptide is derived from A52R. In some embodiments,the peptide is a peptide of S1-S22 (SEQ ID NOs: 228-230; 254-263;265-267; 269; and 288-292). The invention also contemplates a method oftreating ear inflammation in an animal in need or want thereof, themethod comprising administering to the animal a pharmaceuticalcomposition of the invention. The ear inflammation can be associatedwith noise-induced hearing loss, or age-related hearing loss.

The in vivo effectiveness of P13 (SEQ ID NO: 369) was demonstrated usinga mouse model of otitis media (OM). OM is an inflammatory disease of themiddle ear accompanied by fluid accumulation. It is characterized by aninfiltration of leukocytes, macrophages, and mast cells and a release ofinflammatory mediators and enzymes (Reference 21). These mediatorsincrease vascular permeability and secretory activity, and initiate acascade of inflammatory events, resulting in fluid accumulation andmucin secretion (References 26 and 27). The initiation of inflammationin OM has been attributed to a variety of factors, including bacterialor viral infections, Eustachian tube dysfunction, and allergy. However,the evidence points to a bacterial etiology leading to cytokineactivation in the majority of cases. Bacteria have been cultured from upto 40% of effusions and studies have shown bacterial DNA by PCR inapproximately 80% of effusions, often in the absence of viable organismsin culture (Reference 28). The most common bacteria invading the middleear are S. pneumoniae, H. influenzae, and M. catarralis. These threebacteria account for 85% of acute middle ear infections (Reference 27),with S. pneumoniae being the most frequent cause. Initially, livebacteria trigger acute inflammation, which is designed to eliminate thepathogen. During acute infection, interference with the innate immuneresponse would be potentially harmful to the host and can lead tofurther bacterial spread. Acute inflammation initiated by bacterialinfections self-resolves or is treatable by antibiotics. Chronicinflammation involves continued activation of the immune system, oftenby non-viable bacterial products. OM is often prolonged or anti-bioticresistant, suggesting TLR stimulation in the absence of live bacteria.

Treatment of mice with P13 (SEQ ID NO: 369) in the experiments disclosedherein resulted in a significant reduction in bacterial-inducedinflammation in the middle ear. Fluid accumulation, infiltrating cells,and tympanic membrane thickness in the middle ear were all dramaticallyreduced with peptide treatment. Administration of heat-inactivatedbacteria, which have a number of potential TLR ligands, induced aninflammatory response in the middle ear most likely resulting fromactivation of multiple TLRs. The use of heat-inactivated bacteriaallowed for an examination of peptide inhibition of inflammation withoutthe potential for the bacterial spread that can occur in an acuteinfection initiated with live bacteria. The ability of peptide P13 (SEQID NO: 369) to inhibit this response significantly in vivo is consistentwith the in vitro data showing inhibition of cytokine secretion inresponse to multiple TLR ligands used either individually or incombination. In these studies, a single dose of peptide was administeredat the same time as heat-inactivated S. pneumoniae into the middle earsof normal BALB/c mice. The in vitro data also showed inhibition ofcytokine secretion even when peptide P13 (SEQ ID NO: 369) was addedseveral hours after initiation of TLR activation.

In addition to P13 (SEQ ID NO: 369) and the peptides of Table 1, theinvention disclosed herein also contemplates peptides more broadlycharacterized as variants, derivatives, stereoisomers, or analogues ofany peptide of the instant invention. These terms are not exclusive, andcan be contemplated in concert to describe peptides that are describedby one or more of the terms. Many such peptides, not all of which areexpressly disclosed herein, are contemplated as peptides, as componentsof a formulation or pharmaceutical composition, and as elements of themethods and uses of the instant invention.

In some embodiments, the variant, derivative, stereoisomer, or analogueof a peptide of the invention comprises a peptide comprising a peptideof the invention and a poly-argenine sequence. In some embodiments, thevariant, derivative, stereoisomer, or analogue of a peptide of theinvention comprises one or more D-amino acid residues. In someembodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 of theamino acid residues of the variant, derivative, stereoisomer, oranalogue of a peptide of the invention possess the D-configuration. Insome embodiments, all the amino acid residues of the variant,derivative, stereoisomer, or analogue of a peptide of the inventionpossess the D-configuration.

In some embodiments, the variant, derivative, stereoisomer, or analogueof a peptide of the invention comprises one or more D-amino acidresidues in the region of the peptide analogous to or derived from apeptide of the invention. In some embodiments, the region of the peptideanalogous to or derived from P13 (SEQ ID NO: 369) comprises more thanone D-amino acid residue.

In some embodiments, the region of the peptide analogous to or derivedfrom a peptide of the invention comprises a D-amino acid residue. Insome embodiments, the poly-argenine sequence comprises a D-amino acidresidue. In some embodiments, the poly-argenine sequence comprises morethan one D-amino acid residue. In some embodiments, either the region ofthe peptide analogous to or derived from a peptide of the invention orthe poly-argenine sequence comprises a D-amino acid residue. In someembodiments, either the region of the peptide analogous to or derivedfrom a peptide of the invention or the poly-argenine sequence comprisesmore than one D-amino acid residue. In some embodiments, both the regionof the peptide analogous to or derived from a peptide of the inventionand the poly-argenine sequence independently comprise a D-amino acidresidue. In some embodiments, both the region of the peptide analogousto or derived from a peptide of the invention and the poly-argeninesequence independently comprise more than one D-amino acid residue.

In some embodiments comprising a peptide comprising a variant,derivative, stereoisomer, or analogue of a peptide of the inventioncomprising a poly-argenine sequence, the region of the peptide analogousto or derived from P13 (SEQ ID NO: 369) consists of D-amino acidresidues. In some embodiments, the region of the peptide analogous to orderived from a peptide of the invention consists of D-amino acidresidues, and the poly-argenine sequence consists of L-amino acidresidues. In some embodiments, the region of the peptide analogous to orderived from a peptide of the invention consists of D-amino acidresidues, and the poly-argenine sequence comprises one or more D-aminoacid residues.

In some embodiments, the poly-argenine sequence consists of D-amino acidresidues. In some embodiments, the poly-argenine sequence consists ofD-amino acid residues, and the region of the peptide analogous to orderived from a peptide of the invention consists of L-amino acidresidues. In some embodiments, the poly-argenine sequence consists ofD-amino acid residues, and the region of the peptide analogous to orderived from a peptide of the invention comprises one or more D-aminoacid residues.

In some embodiments comprising a peptide comprising a variant,derivative, stereoisomer, or analogue of a peptide of the inventioncomprising a poly-argenine sequence, the peptide consists of D-aminoacid residues.

In some embodiments, a peptide comprises an amino acid residuecomprising a stereogenic side chain, for example, threonine,allo-threonine, isoleucine, or allo-isoleucine. In some embodiments, apeptide comprises a D-allo-threonine, or D-allo-isoleucine residue.

Diseases

The initiation of an inflammatory response to pathogens is a componentof the innate immune response and is designed to control infection.However, the sustained production of inflammatory mediators can lead tochronic inflammation, tissue damage and disease development. Thesignaling cascade initiated by PAMP/TLR interactions and culminating incell activation has been associated with many disease states, includingotitis media, inner ear inflammation, sepsis, autoimmune diseases,asthma, heart disease and cancer (Reference 29). OM is an inflammatorydisease of the middle ear. OM is often prolonged or antibioticresistant; these characteristics suggest TLR stimulation in the absenceof live bacteria. An abnormal TLR signaling response could lead toexaggerated cell-activation responses contributing to sepsis (Reference30 and 31).

Inflammation is also an aspect of autoimmunity, and is hypothesized toplay a role in tissue destruction in diseases such as multiplesclerosis, rheumatoid arthritis and insulin-dependent diabetes mellitus(Reference 32). Cells of the innate immune system have an essential rolein acquired/adaptive immunity. TLR proteins are involved in thematuration and activation of dendritic cells, the antigen-presentingcell type considered most relevant to development of acquired immunity(Reference 33). Allergic asthma is an example of a chronic inflammatorydisease with an adaptive immune response, and the TLR signaling pathwayis implicated in the induction phase of an allergic phenotype (Reference30). Bacterial and viral infections, causing increased inflammatory cellactivation, are the main cause of exacerbations in diseases such asasthma and COPD (chronic obstructive pulmonary disease) (Reference 30).

In some embodiments, the inflammation is caused by a virus, bacteria,fungi, antigen, self-antigen, or a combination thereof. In someembodiments, the inflammation is associated with a virus, bacteria,fungi, antigen, self-antigen, or a combination thereof. In someembodiments, the inflammation is correlated with a virus, bacteria,fungi, antigen, self-antigen, or a combination thereof. In someembodiments, the inflammation is accompanied by a virus, bacteria,fungi, antigen, self-antigen, or a combination thereof. In someembodiments, an organism having the inflammation also has a virus,bacteria, fungi, antigen, self-antigen, or a combination thereof.

In some embodiments, the inflammation is caused by noise ornoise-induced damage. The damage can arise from an isolated incident ofdamaging noise exposure, or from long-term habitual noise exposure.Non-limiting examples of noise attributes that can cause or exacerbateear inflammation and hearing loss include volume, intensity, frequency,and duration. Noise exposure can worsen a pre-existing hearing problem,or can cause hearing loss in an animal that previously enjoyed ordinaryhearing capacity. The hearing loss can be a general lack of sensitivityto sound, or can be limited to specific sounds, frequencies or stimuli.

In some embodiments, the inflammation is caused by age or age-relateddamage. The damage can arise from the natural aging process, or from ahealth condition that promotes tissue degradation analogous to that ofthe aging process. Aging can worsen a pre-existing hearing problem, orcan cause hearing loss in an animal that previously enjoyed ordinaryhearing capacity. Age-related hearing loss also contemplates thetendency of an animal, advanced in age, to be more susceptible to damagefrom external stimuli than an analogous, younger animal. The hearingloss can be a general lack of sensitivity to sound, or can be limited tospecific sounds, frequencies or stimuli.

In some embodiments, a subject's ear or hearing has not been damagedand/or is not inflamed. Such a subject experiences normal hearing.Administration of a peptide of the invention or a composition thereofcan improve the subject's ordinary hearing as described herein.

In some embodiments, the peptides provided herein are administered to asubject for the treatment of inflammation. Non-limiting examples of thecauses of inflammation include viral, bacterial or fungal infection,noise, and age. In some embodiments, the inflammation is a result of aresponse to a self-antigen or any other antigen. In some embodiments,the inflammation is a result of a response to an anti-self-antigen. Insome embodiments, the inflammation is a result of a response to externalstimuli, such as sound.

In some embodiments, the inflammation comprises inflammation of the ear.The inflammation of the ear can be inflammation of the inner ear and/ormiddle ear. In some embodiments, the inflammation comprises otitismedia. In some embodiments, pharmaceutical compositions of the instantinvention are used for the treatment of otitis media.

C3H/HeJ mice, defective in TLR4 signaling, are known to develop chronicotitis media (“COM”) spontaneously. Such mice with inner earinflammation may show sensorineural hearing loss in addition to middleear conductive hearing loss. Histologic examination of the middle andinner ear of C3H/HeJ mice with COM has documented a thickening of themucosal surfaces of the middle ear, thickening of the round windowmembrane, fibrosis, labyrinthitis, and Eustachian tube obstruction.These histologic changes correlate with the histology seen with humantemporal bone from patients with a history of COM and labyrinthitis. Themouse studies have shown that C3H/HeJ mice with COM have gram-negativeKlebsiella bacteria in the middle ear. The analogies between theobservations in the mouse experiments and those in human COM andlabrinthitis patients suggest that mouse experiments with a peptide orpharmaceutical composition of the invention disclosed herein provideresults predictive of what the therapeutic effect would be in a humansubject.

In some embodiments, otitis media is associated with hearing loss orreduced hearing. Administration of a peptide of the invention of apharmaceutical composition thereof can improve the hearing of theaffected organism back to ordinary hearing levels. In some embodiments,administration of a therapeutically-effective amount of a pharmaceuticalcomposition to an organism in need or want thereof improves the hearingof the organism, wherein the organism has both otitis media and lessenedhearing. In some embodiments, the peptide or pharmaceutical compositionis administered topically. In some embodiments, upon administration of apeptide of the invention of a pharmaceutical composition thereof, anorganism with hearing loss recovers hearing faster than hearing would berecovered without administration of the peptide or pharmaceuticalcomposition.

In some embodiments, administration of a therapeutically-effectiveamount of a peptide of the invention or a pharmaceutical compositioncomprising the same to an organism with otitis media, wherein theorganism is in need or want thereof, provides therapeutic relief of asymptom of otitis media. Non-limiting examples of the symptoms of otitismedia include otalgia (pain), otorrhea, fever, irritability, anorexia,vomiting, hearing loss, or diarrhea. In some embodiments, the symptom ispain. In some embodiments, the symptom is hearing loss.

In some embodiments, the inflammation comprises inflammation of theskin, joints, muscular tissue, brain, or connective tissue. In someembodiments, pharmaceutical compositions of the instant invention areused for the treatment of inflammation of the skin, joints, musculartissue, brain, or connective tissue.

In some embodiments, the inflammation comprises arthritis, dermatitis,Lupus erythematosus, meningitis, or psoriasis. In some embodiments, thearthritis comprises osteoarthritis, rheumatoid arthritis, septicarthritis, gout, pseudo-gout, juvenile idiopathic arthritis, Still'sdisease, or ankylosing spondylitis. In some embodiments, the dermatitiscomprises spongiotic dermatitis, childhood eczema, allergic contactdermatitis, seborrhoeic dermatitis, dyshidrotic dermatitis, urticaria,vesicular or bullous dermatitis, or papular urticaria. In someembodiments, the psoriasis comprises plaque psoriasis, flexuralpsoriasis, guttate psoriasis, pustular psoriasis, nail psoriasis,psoriatic arthritis, or erythrodermic psoriasis.

In some embodiments, the administration comprises topical application.In some embodiments, the administration comprises topical application tothe skin, hair, outer ear, tympanic membrane, nasal cavity, buccalcavity, or sublingual cavity.

In some embodiments, the peptides of the invention and pharmaceuticalcomposition comprising the same are effective for the treatment ofsinusitis. In some embodiments, administration of a pharmaceuticalcomposition of the invention to an organism in need or want thereofprovides a therapeutic effect on sinusitis or a symptom thereof.Non-limiting examples of symptoms of sinusitis include stuffy or runnynose, nasal discharge, bloody nasal discharge, sneezing, coughing, nasalpain, headache, postnasal drip, itchy face, diminished scent or tastesenses, bad breath, fever, chill, dental pain, or face pain. In someembodiments, a pharmaceutical composition of the invention isadministered as an aerosol, vapor, spray, or mist.

Therapeutic Uses

Each of U.S. patent application Ser. No. 12/794,185 (now U.S.Publication No. US20100317564) and International Patent Application No.PCT/US2010/037443 (now International Publication No. WO2010141845) isincorporated by reference in its entirety for the teachings of peptideshaving anti-inflammatory and related therapeutic effects.

A, “patient,” “subject,” or “host,” to be treated with a pharmaceuticalcomposition of the present invention may mean either a human ornon-human animal. In some embodiments, the subject is human. Thepeptides of the present invention are useful in the treatment of suchdiseases and disorders such as but not limited to those involvinginflammation and hearing loss. In one embodiment, the peptides andpharmaceutical compositions of the present invention may be used in themanufacture of a medicament for any number of uses, including, forexample, treating any disease or other treatable condition of a patient.

A, “therapeutic effect,” as the term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit is achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the patient, notwithstanding that the patient may still beafflicted with the underlying disorder. For prophylactic benefit, thecompositions may be administered to a patient at risk of developing aparticular disease, or to a patient reporting one or more of thephysiological symptoms of a disease, even though a diagnosis of thisdisease may not have been made. A prophylactic effect includes delayingor eliminating the appearance of a disease or condition, delaying oreliminating the onset of symptoms of a disease or condition, slowing,halting, or reversing the progression of a disease or condition, or anycombination thereof.

Tissue damage resulting from noise-induced trauma can initiate toll-likereceptor signaling, which causes inflammation that exacerbates hearingloss. The peptides described herein are suitable to inhibit thesignaling, thereby inhibiting secretion of TNF-α, and providing atherapeutic effect to a subject suffering from noise-induced hearingloss.

Necrotic cell death is associated with the release of danger signals,which can stimulate the immune system through toll-like receptors. Thisstimulation can lead to inflammation, which can cause or aggravatehearing loss. Necrotic cell death occurs in animals during the naturalaging process, and provides a pathway for age-related hearing loss. Thepeptides described herein are suitable to inhibit the stimulation,thereby inhibiting secretion of TNF-α, and providing a therapeuticeffect to a subject suffering from age-related hearing loss.

The invention also contemplates improvement of normal hearing in asubject using any peptide disclosed herein. Normal hearing is auditoryfunction that has not been damaged or degraded. Administration of apeptide of the invention to a subject in need or want of improved normalhearing can result in the improvement of hearing as described herein.

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of Formula (I) or Formula(II) to a subject in need or want thereof,(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (I). In someembodiments, the peptide is a peptide of Formula (II). In someembodiments, the peptide is a peptide of either Formula (I) or Formula(II).

In some embodiments, the peptide is a stereoisomer of Formula (I) orFormula (II). A stereoisomer of Formula (I) or Formula (II) can be anytype of stereoisomer described herein, for example, a peptide possessingone or more D-amino acid residues. A D-amino acid residue can be presentin any or all of tran^(N), pep^(N), X¹⁻¹¹, pep^(C), and tran^(C). Anynumber of amino acid residues can possess the D-configuration, up to,for example, every stereogenic amino acid residue in the peptide.

In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, x is 1, 2, 3, 4, or 5. In some embodiments, x is 1, 2, or3. In some embodiments, x is 1 or 2. In some embodiments, x is 1. Insome embodiments, x is 2.

Non-limiting examples of acidic amino acid residues include residues ofaspartic acid (D); glutamic acid (E); and any synthetic amino acid witha side chain possessing a carboxylic acid functional group. In someembodiments, an acidic amino acid residue is aspartic acid (D) orglutamic acid (E).

Non-limiting examples of basic amino acid residues include residues oflysine (K); arginine (R); histidine (H); and any synthetic amino acidwith a side chain possessing a nitrogen atom that is capable of beingprotonated at physiological pH. In some embodiments, a basic amino acidresidue is lysine (K); arginine (R); or histidine (H).

Non-limiting examples of aromatic amino acid residues include residuesof phenylalanine (F); tryptophan (W); histidine (H); tyrosine (Y) andany synthetic amino acid with a side chain possessing an aromatic ring.In some embodiments, an aromatic amino acid residue is phenylalanine(F); tryptophan (W); histidine (H); or tyrosine (Y). In someembodiments, an aromatic amino acid residue is phenylalanine (F);tryptophan (W); or tyrosine (Y).

Pep^(N) and pep^(C) independently are peptide sequences or are absent.The peptide sequences can be natural, unnatural, or synthetic.

Tran^(N) and tran^(C) independently are transducing sequences asdescribed herein or are absent.

Cap^(N) is a capping group at the N-terminus of a peptide. When twocap^(N) groups are attached to the same nitrogen, the two groups can bethe same or different. Non-limiting examples of cap^(N) include H,alkyl, aryl, aralkyl, an acyl group, an alkoxycarbonyl group, anaryloxycarbonyl group, and an aminocarbonyl group. A cap^(N) grouptogether with the nitrogen atom to which the cap^(N) group is bound canform, for example, an amide, a carbamate, a urethane, a heterocycle, oran amine. Two cap^(N) groups bound to the same nitrogen atom can formtogether with the nitrogen atom a heterocycle.

Cap^(C) is a capping group at the C-terminus of a peptide. Non-limitingexamples of cap^(C) groups include OH, alkoxy, aryloxy, arylalkoxy,amino, alkylamino, dialkylamino, and a heterocycle. A cap^(C) grouptogether with the carbonyl to which the cap^(C) group is bound can form,for example, a carboxylic acid, an ester, or an amide.

In some embodiments, cap^(N) is H. In some embodiments, cap^(C) is OH.In some embodiments, cap^(N) is H and cap^(C) is OH.

Any side chain of any amino acid residue can be capped with a cappinggroup. Non-limiting examples of side chain functional groups that can becapped include a hydroxyl group, a thiol group, a carboxylic acid, anamide, an amino group, an imidazole group, and a guanadino group. Forexamples of capping groups, see GREENE'S P ROTECTIVE GROUPS IN ORGANICSYNTHESIS, 4th Ed. (Wiley 2006) (1980) and PROTECTING GROUPS, 3d Ed.(Thieme 2005) (1994), each of which is incorporated by reference in itsentirety.

Non-limiting examples of suitable capping groups for a hydroxyl groupinclude alkyl, haloalkyl, aryl, aralkyl, and acyl groups.

Non-limiting examples of suitable capping groups for a thiol groupinclude alkyl, haloalkyl, aryl, aralkyl, acyl, carboxyalkyl,carbamidoalkyl, and acetamidoalkyl groups.

Non-limiting examples of suitable capping groups for a carboxylic acidgroup include alkyl, haloalkyl, aryl, and aralkyl groups.

Non-limiting examples of suitable capping groups for an amino groupinclude examples as disclosed herein for cap^(N).

Non-limiting examples of alkyl include straight, branched, and cyclicalkyl groups. Non-limiting examples of straight alkyl groups includemethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, anddecyl.

Branched alkyl groups include any straight alkyl group substituted withany number of alkyl groups. Non-limiting examples of branched alkylgroups include isopropyl, isobutyl, sec-butyl, and t-butyl.

Non-limiting examples of cyclic alkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctylgroups. Cyclic alkyl groups also include fused-, bridged-, andspiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclicalkyl group can be substituted with any number of straight or branchedalkyl groups.

A halo-alkyl group can be any alkyl group substituted with any number ofhalogen atoms, for example, fluorine, chlorine, bromine, and iodineatoms.

An alkoxy group can be, for example, an oxygen atom substituted with anyalkyl group.

An aryl group can be heterocyclic or non-heterocyclic. An aryl group canbe monocyclic or polycyclic. An aryl group can be substituted with anynumber of alkyl groups and halogen atoms. Non-limiting examples of arylgroups include phenyl, toluoyl, naphthyl, pyrrolyl, pyridyl, imidazolyl,thiophenyl, and furyl.

An aryloxy group can be, for example, an oxygen atom substituted withany aryl group, such as phenoxy.

An aralkyl group can be, for example, any alkyl group substituted withany aryl group, such as benzyl.

An arylalkoxy group can be, for example, an oxygen atom substituted withany aralkyl group, such as benzyloxy.

A heterocycle can be any ring containing a ring atom that is not carbon.A heterocycle can be substituted with any number of alkyl groups andhalogen atoms. Non-limiting examples of heterocycles include pyrrole,pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine,imidazole, thiophene, furan, tetrahydrofuran, pyran, andtetrahydropyran.

An acyl group can be, for example, a carbonyl group substituted with analkyl, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle.Non-limiting examples of acyl include acetyl, benzoyl,benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; 363-369; and 378. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 131-175; 177-186;317-361; and 363-368. In some embodiments, the peptide is a peptide ofany one of SEQ ID NOS: 131-175. In some embodiments, the peptide is apeptide of any one of SEQ ID NOS: 177-186. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 317-361. In someembodiments, the peptide is a peptide of any one of SEQ ID NOS: 363-369and 378. In some embodiments, the peptide is SEQ ID NO: 369. In someembodiments, the peptide is SEQ ID NO: 378. In some embodiments, thepeptide is not SEQ ID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of Formula (III) orFormula (IV) to a subject in need or want thereof,(cap^(N))(cap^(N))N-tran^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(III),(cap^(N))(cap^(N))N-tran^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(IV), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; X¹ is A, K, an acidic amino acid residue, or is absent; X² is A,I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I, Y, or a basicamino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T, or Y; X⁷ isA, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic amino acid residue;X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C, M, S,α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or is absent; X¹²is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy, aryloxy,arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and eachamino acid residue side chain is independently optionally capped with acapping group, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is a peptide of Formula (III). In someembodiments, the peptide is a peptide of Formula (IV). In someembodiments, the peptide is a peptide of either Formula (III) or Formula(IV)

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of Formula (V) or Formula(VI) to a subject in need or want thereof,(cap^(N))(cap^(N))N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(V),(cap^(N))(cap^(N))N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(VI), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(C) is a transducing sequence or absent; X¹ is A, K, an acidicamino acid residue, or is absent; X² is A, I, L, or V; X³ is A, D, I, L,P, or V; X⁴ is A, E, I, Y, or a basic amino acid residue; X⁵ is A, I, L,or V; X⁶ is A, G, S, T, or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T,or an aromatic amino acid residue; X⁹ is A, K, or an acidic amino acidresidue; X¹⁰ is A, C, M, S, α-aminobutyric acid, or norvaline; X¹¹ is A,I, L, V, or is absent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C)is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, ora heterocycle; and each amino acid residue side chain is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (V). In someembodiments, the peptide is a peptide of Formula (VI). In someembodiments, the peptide is a peptide of either Formula (V) or Formula(VI)

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide to a subject in need orwant thereof, wherein the peptide comprises: IGLCA (SEQ ID NO: 207);YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276);YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO:305), wherein each terminus and each amino acid residue side chain ofthe peptide is independently optionally capped with a capping group, ora stereoisomer or pharmaceutically-acceptable salt of any of theforegoing.

A stereoisomer can be any form of stereoisomer described herein.

The optional capping groups on the N-terminus, the C-terminus, and eachamino acid residue side chain can be any suitable capping groupdescribed herein.

The peptide can further comprise a transducing sequence. The transducingsequence can be any transducing sequence described herein. Thetransducing sequence can be positioned at either the N- or theC-terminus of the peptide. In some embodiments, the transducing sequenceis positioned at the C-terminus of the peptide. The transducing sequencecan be any poly-arginine sequence described herein.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; 379; 380; and 381-396. In some embodiments, the peptideis a peptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396. Insome embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130. In some embodiments, the peptide is a peptide of any one of SEQID NOS: 187-316. In some embodiments, the peptide is a peptide of anyone of SEQ ID NOS: 381-396. In some embodiments, the peptide is SEQ IDNO: 379. In some embodiments, the peptide is SEQ ID NO: 380. In someembodiments, the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of Formula (I) or Formula(II) to a subject in need or want thereof,(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (I). In someembodiments, the peptide is a peptide of Formula (II). In someembodiments, the peptide is a peptide of either Formula (I) or Formula(II).

In some embodiments, the peptide is a stereoisomer of Formula (I) orFormula (II). A stereoisomer of Formula (I) or Formula (II) can be anytype of stereoisomer described herein, for example, a peptide possessingone or more D-amino acid residues. A D-amino acid residue can be presentin any or all of tran^(N), pep^(N), X¹⁻¹¹, pep^(C), and tran^(C). Anynumber of amino acid residues can possess the D-configuration, up to,for example, every stereogenic amino acid residue in the peptide.

In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, x is 1, 2, 3, 4, or 5. In some embodiments, x is 1, 2, or3. In some embodiments, x is 1 or 2. In some embodiments, x is 1. Insome embodiments, x is 2.

Non-limiting examples of acidic amino acid residues include residues ofaspartic acid (D); glutamic acid (E); and any synthetic amino acid witha side chain possessing a carboxylic acid functional group. In someembodiments, an acidic amino acid residue is aspartic acid (D) orglutamic acid (E).

Non-limiting examples of basic amino acid residues include residues oflysine (K); arginine (R); histidine (H); and any synthetic amino acidwith a side chain possessing a nitrogen atom that is capable of beingprotonated at physiological pH. In some embodiments, a basic amino acidresidue is lysine (K); arginine (R); or histidine (H).

Non-limiting examples of aromatic amino acid residues include residuesof phenylalanine (F); tryptophan (W); histidine (H); tyrosine (Y) andany synthetic amino acid with a side chain possessing an aromatic ring.In some embodiments, an aromatic amino acid residue is phenylalanine(F); tryptophan (W); histidine (H); or tyrosine (Y). In someembodiments, an aromatic amino acid residue is phenylalanine (F);tryptophan (W); or tyrosine (Y).

Pep^(N) and pep^(C) independently are peptide sequences or are absent.The peptide sequences can be natural, unnatural, or synthetic.

Tran^(N) and tran^(C) independently are transducing sequences asdescribed herein or are absent.

Cap^(N) is a capping group at the N-terminus of a peptide. When twocap^(N) groups are attached to the same nitrogen, the two groups can bethe same or different. Non-limiting examples of cap^(N) include H,alkyl, aryl, aralkyl, an acyl group, an alkoxycarbonyl group, anaryloxycarbonyl group, and an aminocarbonyl group. A cap^(N) grouptogether with the nitrogen atom to which the cap^(N) group is bound canform, for example, an amide, a carbamate, a urethane, a heterocycle, oran amine. Two cap^(N) groups bound to the same nitrogen atom can formtogether with the nitrogen atom a heterocycle.

Cap^(C) is a capping group at the C-terminus of a peptide. Non-limitingexamples of cap^(C) groups include OH, alkoxy, aryloxy, arylalkoxy,amino, alkylamino, dialkylamino, and a heterocycle. A cap^(C) grouptogether with the carbonyl to which the cap^(C) group is bound can form,for example, a carboxylic acid, an ester, or an amide.

In some embodiments, cap^(N) is H. In some embodiments, cap^(C) is OH.In some embodiments, cap^(N) is H and cap^(C) is OH.

Any side chain of any amino acid residue can be capped with any suitablecapping group described herein.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; 363-369; and 378. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 131-175; 177-186;317-361; and 363-368. In some embodiments, the peptide is a peptide ofany one of SEQ ID NOS: 131-175. In some embodiments, the peptide is apeptide of any one of SEQ ID NOS: 177-186. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 317-361. In someembodiments, the peptide is a peptide of any one of SEQ ID NOS: 363-369and 378. In some embodiments, the peptide is SEQ ID NO: 369. In someembodiments, the peptide is SEQ ID NO: 378. In some embodiments, thepeptide is not SEQ ID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of Formula (III) orFormula (IV) to a subject in need or want thereof,(cap^(N))(cap^(N))N-tran^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(III),(cap^(N))(cap^(N))N-tran^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(IV), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; X¹ is A, K, an acidic amino acid residue, or is absent; X² is A,I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I, Y, or a basicamino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T, or Y; X⁷ isA, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic amino acid residue;X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C, M, S,α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or is absent; X¹²is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy, aryloxy,arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and eachamino acid residue side chain is independently optionally capped with acapping group, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is a peptide of Formula (III). In someembodiments, the peptide is a peptide of Formula (IV). In someembodiments, the peptide is a peptide of either Formula (III) or Formula(IV).

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of Formula (V) or Formula(VI) to a subject in need or want thereof,(cap^(N))(cap^(N))N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(V),(cap^(N))(cap^(N))N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(VI), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(C) is a transducing sequence or absent; X¹ is A, K, an acidicamino acid residue, or is absent; X² is A, I, L, or V; X³ is A, D, I, L,P, or V; X⁴ is A, E, I, Y, or a basic amino acid residue; X⁵ is A, I, L,or V; X⁶ is A, G, S, T, or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T,or an aromatic amino acid residue; X⁹ is A, K, or an acidic amino acidresidue; X¹⁰ is A, C, M, S, α-aminobutyric acid, or norvaline; X¹¹ is A,I, L, V, or is absent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C)is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, ora heterocycle; and each amino acid residue side chain is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (V). In someembodiments, the peptide is a peptide of Formula (VI). In someembodiments, the peptide is a peptide of either Formula (V) or Formula(VI).

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide to a subject in need orwant thereof, wherein the peptide comprises: IGLCA (SEQ ID NO: 207);YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276);YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO:305), wherein each terminus and each amino acid residue side chain ofthe peptide is independently optionally capped with a capping group, ora stereoisomer or pharmaceutically-acceptable salt of any of theforegoing.

A stereoisomer can be any form of stereoisomer described herein.

The optional capping groups on the N-terminus, the C-terminus, and eachamino acid residue side chain can be any suitable capping groupdescribed herein.

The peptide can further comprise a transducing sequence. The transducingsequence can be any transducing sequence described herein. Thetransducing sequence can be positioned at either the N- or theC-terminus of the peptide. In some embodiments, the transducing sequenceis positioned at the C-terminus of the peptide. The transducing sequencecan be any poly-arginine sequence described herein.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; 379; 380; and 381-396. In some embodiments, the peptideis a peptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396. Insome embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130. In some embodiments, the peptide is a peptide of any one of SEQID NOS: 187-316. In some embodiments, the peptide is a peptide of anyone of SEQ ID NOS: 381-396. In some embodiments, the peptide is SEQ IDNO: 379. In some embodiments, the peptide is SEQ ID NO: 380. In someembodiments, the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a method of improving normalhearing, the method comprising administering a therapeutically-effectiveamount of a peptide of Formula (I) or Formula (II) to a subject in needor want thereof,(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (I). In someembodiments, the peptide is a peptide of Formula (II). In someembodiments, the peptide is a peptide of either Formula (I) or Formula(II).

In some embodiments, the peptide is a stereoisomer of Formula (I) orFormula (II). A stereoisomer of Formula (I) or Formula (II) can be anytype of stereoisomer described herein, for example, a peptide possessingone or more D-amino acid residues. A D-amino acid residue can be presentin any or all of tran^(N), pep^(N), X¹⁻¹¹, pep^(C), and tran^(C). Anynumber of amino acid residues can possess the D-configuration, up to,for example, every stereogenic amino acid residue in the peptide.

In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, x is 1, 2, 3, 4, or 5. In some embodiments, x is 1, 2, or3. In some embodiments, x is 1 or 2. In some embodiments, x is 1. Insome embodiments, x is 2.

Non-limiting examples of acidic amino acid residues include residues ofaspartic acid (D); glutamic acid (E); and any synthetic amino acid witha side chain possessing a carboxylic acid functional group. In someembodiments, an acidic amino acid residue is aspartic acid (D) orglutamic acid (E).

Non-limiting examples of basic amino acid residues include residues oflysine (K); arginine (R); histidine (H); and any synthetic amino acidwith a side chain possessing a nitrogen atom that is capable of beingprotonated at physiological pH. In some embodiments, a basic amino acidresidue is lysine (K); arginine (R); or histidine (H).

Non-limiting examples of aromatic amino acid residues include residuesof phenylalanine (F); tryptophan (W); histidine (H); tyrosine (Y) andany synthetic amino acid with a side chain possessing an aromatic ring.In some embodiments, an aromatic amino acid residue is phenylalanine(F); tryptophan (W); histidine (H); or tyrosine (Y). In someembodiments, an aromatic amino acid residue is phenylalanine (F);tryptophan (W); or tyrosine (Y).

Pep^(N) and pep^(C) independently are peptide sequences or are absent.The peptide sequences can be natural, unnatural, or synthetic.

Tran^(N) and tran^(C) independently are transducing sequences asdescribed herein or are absent.

Cap^(N) is a capping group at the N-terminus of a peptide. When twocap^(N) groups are attached to the same nitrogen, the two groups can bethe same or different. Non-limiting examples of cap^(N) include H,alkyl, aryl, aralkyl, an acyl group, an alkoxycarbonyl group, anaryloxycarbonyl group, and an aminocarbonyl group. A cap^(N) grouptogether with the nitrogen atom to which the cap^(N) group is bound canform, for example, an amide, a carbamate, a urethane, a heterocycle, oran amine. Two cap^(N) groups bound to the same nitrogen atom can formtogether with the nitrogen atom a heterocycle.

Cap^(C) is a capping group at the C-terminus of a peptide. Non-limitingexamples of cap^(C) groups include OH, alkoxy, aryloxy, arylalkoxy,amino, alkylamino, dialkylamino, and a heterocycle. A cap^(C) grouptogether with the carbonyl to which the cap^(C) group is bound can form,for example, a carboxylic acid, an ester, or an amide.

In some embodiments, cap^(N) is H. In some embodiments, cap^(C) is OH.In some embodiments, cap^(N) is H and cap^(C) is OH.

Any side chain of any amino acid residue can be capped with any suitablecapping group described herein.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; 363-369; and 378. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 131-175; 177-186;317-361; and 363-368. In some embodiments, the peptide is a peptide ofany one of SEQ ID NOS: 131-175. In some embodiments, the peptide is apeptide of any one of SEQ ID NOS: 177-186. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 317-361. In someembodiments, the peptide is a peptide of any one of SEQ ID NOS: 363-369and 378. In some embodiments, the peptide is SEQ ID NO: 369. In someembodiments, the peptide is SEQ ID NO: 378. In some embodiments, thepeptide is not SEQ ID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a method of improving normalhearing, the method comprising administering a therapeutically-effectiveamount of a peptide of Formula (III) or Formula (IV) to a subject inneed or want thereof,(cap^(N))(cap^(N))N-tran^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(III),(cap^(N))(cap^(N))N-tran^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(IV), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; X¹ is A, K, an acidic amino acid residue, or is absent; X² is A,I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I, Y, or a basicamino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T, or Y; X⁷ isA, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic amino acid residue;X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C, M, S,α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or is absent; X¹²is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy, aryloxy,arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and eachamino acid residue side chain is independently optionally capped with acapping group, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is a peptide of Formula (III). In someembodiments, the peptide is a peptide of Formula (IV). In someembodiments, the peptide is a peptide of either Formula (III) or Formula(IV).

In some embodiments, the invention provides a method of improving normalhearing, the method comprising administering a therapeutically-effectiveamount of a peptide of Formula (V) or Formula (VI) to a subject in needor want thereof,(cap^(N))(cap^(N))N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(V),(cap^(N))(cap^(N))N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(VI), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(C) is a transducing sequence or absent; X¹ is A, K, an acidicamino acid residue, or is absent; X² is A, I, L, or V; X³ is A, D, I, L,P, or V; X⁴ is A, E, I, Y, or a basic amino acid residue; X⁵ is A, I, L,or V; X⁶ is A, G, S, T, or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T,or an aromatic amino acid residue; X⁹ is A, K, or an acidic amino acidresidue; X¹⁰ is A, C, M, S, α-aminobutyric acid, or norvaline; X¹¹ is A,I, L, V, or is absent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C)is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, ora heterocycle; and each amino acid residue side chain is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (V). In someembodiments, the peptide is a peptide of Formula (VI). In someembodiments, the peptide is a peptide of either Formula (V) or Formula(VI).

In some embodiments, the invention provides a method of improving normalhearing, the method comprising administering a therapeutically-effectiveamount of a peptide to a subject in need or want thereof, wherein thepeptide comprises: IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227); LFNEI(SEQ ID NO: 252); EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287); RIKYG(SEQ ID NO: 304); or EEYFM (SEQ ID NO: 305), wherein each terminus andeach amino acid residue side chain of the peptide is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing.

A stereoisomer can be any form of stereoisomer described herein.

The optional capping groups on the N-terminus, the C-terminus, and eachamino acid residue side chain can be any suitable capping groupdescribed herein.

The peptide can further comprise a transducing sequence. The transducingsequence can be any transducing sequence described herein. Thetransducing sequence can be positioned at either the N- or theC-terminus of the peptide. In some embodiments, the transducing sequenceis positioned at the C-terminus of the peptide. The transducing sequencecan be any poly-arginine sequence described herein.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; 379; 380; and 381-396. In some embodiments, the peptideis a peptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396. Insome embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130. In some embodiments, the peptide is a peptide of any one of SEQID NOS: 187-316. In some embodiments, the peptide is a peptide of anyone of SEQ ID NOS: 381-396. In some embodiments, the peptide is SEQ IDNO: 379. In some embodiments, the peptide is SEQ ID NO: 380. In someembodiments, the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the compound is a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (I). In someembodiments, the peptide is a peptide of Formula (II). In someembodiments, the peptide is a peptide of either Formula (I) or Formula(II).

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; 363-369; and 378. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 131-175; 177-186;317-361; and 363-368. In some embodiments, the peptide is a peptide ofany one of SEQ ID NOS: 131-175. In some embodiments, the peptide is apeptide of any one of SEQ ID NOS: 177-186. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 317-361. In someembodiments, the peptide is a peptide of any one of SEQ ID NOS: 363-369and 378. In some embodiments, the peptide is SEQ ID NO: 369. In someembodiments, the peptide is SEQ ID NO: 378. In some embodiments, thepeptide is not SEQ ID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the compound is a peptide of Formula (III) or Formula(IV),(cap^(N))(cap^(N))N-tran^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(III),(cap^(N))(cap^(N))N-tran^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(IV), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; X¹ is A, K, an acidic amino acid residue, or is absent; X² is A,I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I, Y, or a basicamino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T, or Y; X⁷ isA, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic amino acid residue;X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C, M, S,α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or is absent; X¹²is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy, aryloxy,arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and eachamino acid residue side chain is independently optionally capped with acapping group, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is a peptide of Formula (III). In someembodiments, the peptide is a peptide of Formula (IV). In someembodiments, the peptide is a peptide of either Formula (III) or Formula(IV).

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the compound is a peptide of Formula (V) or Formula (VI),(cap^(N))(cap^(N))N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(V),(cap^(N))(cap^(N))N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(VI), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(C) is a transducing sequence or absent; X¹ is A, K, an acidicamino acid residue, or is absent; X² is A, I, L, or V; X³ is A, D, I, L,P, or V; X⁴ is A, E, I, Y, or a basic amino acid residue; X⁵ is A, I, L,or V; X⁶ is A, G, S, T, or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T,or an aromatic amino acid residue; X⁹ is A, K, or an acidic amino acidresidue; X¹⁰ is A, C, M, S, α-aminobutyric acid, or norvaline; X¹¹ is A,I, L, V, or is absent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C)is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, ora heterocycle; and each amino acid residue side chain is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (V). In someembodiments, the peptide is a peptide of Formula (VI). In someembodiments, the peptide is a peptide of either Formula (V) or Formula(VI).

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the compound is a peptide comprising: IGLCA (SEQ ID NO:207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO:276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ IDNO: 305), wherein each terminus and each amino acid residue side chainof the peptide is independently optionally capped with a capping group,or a stereoisomer or pharmaceutically-acceptable salt of any of theforegoing.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; 379; 380; and 381-396. In some embodiments, the peptideis a peptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396. Insome embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130. In some embodiments, the peptide is a peptide of any one of SEQID NOS: 187-316. In some embodiments, the peptide is a peptide of anyone of SEQ ID NOS: 381-396. In some embodiments, the peptide is SEQ IDNO: 379. In some embodiments, the peptide is SEQ ID NO: 380. In someembodiments, the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the compound is a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (I). In someembodiments, the peptide is a peptide of Formula (II). In someembodiments, the peptide is a peptide of either Formula (I) or Formula(II).

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; 363-369; and 378. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 131-175; 177-186;317-361; and 363-368. In some embodiments, the peptide is a peptide ofany one of SEQ ID NOS: 131-175. In some embodiments, the peptide is apeptide of any one of SEQ ID NOS: 177-186. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 317-361. In someembodiments, the peptide is a peptide of any one of SEQ ID NOS: 363-369and 378. In some embodiments, the peptide is SEQ ID NO: 369. In someembodiments, the peptide is SEQ ID NO: 378. In some embodiments, thepeptide is not SEQ ID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the compound is a peptide of Formula (III) or Formula(IV),(cap^(N))(cap^(N))N-tran^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(III),(cap^(N))(cap^(N))N-tran^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(IV), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; X¹ is A, K, an acidic amino acid residue, or is absent; X² is A,I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I, Y, or a basicamino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T, or Y; X⁷ isA, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic amino acid residue;X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C, M, S,α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or is absent; X¹²is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy, aryloxy,arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and eachamino acid residue side chain is independently optionally capped with acapping group, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is a peptide of Formula (III). In someembodiments, the peptide is a peptide of Formula (IV). In someembodiments, the peptide is a peptide of either Formula (III) or Formula(IV).

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the compound is a peptide of Formula (V) or Formula (VI),(cap^(N))(cap^(N))N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(V),(cap^(N))(cap^(N))N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(VI), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(C) is a transducing sequence or absent; X¹ is A, K, an acidicamino acid residue, or is absent; X² is A, I, L, or V; X³ is A, D, I, L,P, or V; X⁴ is A, E, I, Y, or a basic amino acid residue; X⁵ is A, I, L,or V; X⁶ is A, G, S, T, or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T,or an aromatic amino acid residue; X⁹ is A, K, or an acidic amino acidresidue; X¹⁰ is A, C, M, S, α-aminobutyric acid, or norvaline; X¹¹ is A,I, L, V, or is absent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C)is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, ora heterocycle; and each amino acid residue side chain is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (V). In someembodiments, the peptide is a peptide of Formula (VI). In someembodiments, the peptide is a peptide of either Formula (V) or Formula(VI).

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the compound is a peptide comprising: IGLCA (SEQ ID NO:207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO:276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ IDNO: 305), wherein each terminus and each amino acid residue side chainof the peptide is independently optionally capped with a capping group,or a stereoisomer or pharmaceutically-acceptable salt of any of theforegoing.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; 379; 380; and 381-396. In some embodiments, the peptideis a peptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396. Insome embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130. In some embodiments, the peptide is a peptide of any one of SEQID NOS: 187-316. In some embodiments, the peptide is a peptide of anyone of SEQ ID NOS: 381-396. In some embodiments, the peptide is SEQ IDNO: 379. In some embodiments, the peptide is SEQ ID NO: 380. In someembodiments, the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the improvement of normal hearing,wherein the compound is a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (I). In someembodiments, the peptide is a peptide of Formula (II). In someembodiments, the peptide is a peptide of either Formula (I) or Formula(II).

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; 363-369; and 378. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 131-175; 177-186;317-361; and 363-368. In some embodiments, the peptide is a peptide ofany one of SEQ ID NOS: 131-175. In some embodiments, the peptide is apeptide of any one of SEQ ID NOS: 177-186. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 317-361. In someembodiments, the peptide is a peptide of any one of SEQ ID NOS: 363-369and 378. In some embodiments, the peptide is SEQ ID NO: 369. In someembodiments, the peptide is SEQ ID NO: 378. In some embodiments, thepeptide is not SEQ ID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the improvement of normal hearing,wherein the compound is a peptide of Formula (III) or Formula (IV),(cap^(N))(cap^(N))N-tran^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(III),(cap^(N))(cap^(N))N-tran^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(IV), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; X¹ is A, K, an acidic amino acid residue, or is absent; X² is A,I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I, Y, or a basicamino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T, or Y; X⁷ isA, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic amino acid residue;X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C, M, S,α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or is absent; X¹²is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy, aryloxy,arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and eachamino acid residue side chain is independently optionally capped with acapping group, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is a peptide of Formula (III). In someembodiments, the peptide is a peptide of Formula (IV). In someembodiments, the peptide is a peptide of either Formula (III) or Formula(IV).

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the improvement of normal hearing,wherein the compound is a peptide of Formula (V) or Formula (VI),(cap^(N))(cap^(N))N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(V),(cap^(N))(cap^(N))N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(VI), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(C) is a transducing sequence or absent; X¹ is A, K, an acidicamino acid residue, or is absent; X² is A, I, L, or V; X³ is A, D, I, L,P, or V; X⁴ is A, E, I, Y, or a basic amino acid residue; X⁵ is A, I, L,or V; X⁶ is A, G, S, T, or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T,or an aromatic amino acid residue; X⁹ is A, K, or an acidic amino acidresidue; X¹⁰ is A, C, M, S, α-aminobutyric acid, or norvaline; X¹¹ is A,I, L, V, or is absent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C)is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, ora heterocycle; and each amino acid residue side chain is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (V). In someembodiments, the peptide is a peptide of Formula (VI). In someembodiments, the peptide is a peptide of either Formula (V) or Formula(VI).

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the improvement of normal hearing,wherein the compound is a peptide comprising: IGLCA (SEQ ID NO: 207);YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276);YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO:305), wherein each terminus and each amino acid residue side chain ofthe peptide is independently optionally capped with a capping group, ora stereoisomer or pharmaceutically-acceptable salt of any of theforegoing.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; 379; 380; and 381-396. In some embodiments, the peptideis a peptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396. Insome embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130. In some embodiments, the peptide is a peptide of any one of SEQID NOS: 187-316. In some embodiments, the peptide is a peptide of anyone of SEQ ID NOS: 381-396. In some embodiments, the peptide is SEQ IDNO: 379. In some embodiments, the peptide is SEQ ID NO: 380. In someembodiments, the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a compound for use in thetreatment of noise-induced hearing loss, wherein the compound is apeptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (I). In someembodiments, the peptide is a peptide of Formula (II). In someembodiments, the peptide is a peptide of either Formula (I) or Formula(II).

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; 363-369; and 378. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 131-175; 177-186;317-361; and 363-368. In some embodiments, the peptide is a peptide ofany one of SEQ ID NOS: 131-175. In some embodiments, the peptide is apeptide of any one of SEQ ID NOS: 177-186. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 317-361. In someembodiments, the peptide is a peptide of any one of SEQ ID NOS: 363-369and 378. In some embodiments, the peptide is SEQ ID NO: 369. In someembodiments, the peptide is SEQ ID NO: 378. In some embodiments, thepeptide is not SEQ ID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a compound for use in thetreatment of noise-induced hearing loss, wherein the compound is apeptide of Formula (III) or Formula (IV),(cap^(N))(cap^(N))N-tran^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(III),(cap^(N))(cap^(N))N-tran^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(IV), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; X¹ is A, K, an acidic amino acid residue, or is absent; X² is A,I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I, Y, or a basicamino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T, or Y; X⁷ isA, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic amino acid residue;X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C, M, S,α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or is absent; X¹²is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy, aryloxy,arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and eachamino acid residue side chain is independently optionally capped with acapping group, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is a peptide of Formula (III). In someembodiments, the peptide is a peptide of Formula (IV). In someembodiments, the peptide is a peptide of either Formula (III) or Formula(IV).

In some embodiments, the invention provides a compound for use in thetreatment of noise-induced hearing loss, wherein the compound is apeptide of Formula (V) or Formula (VI),(cap^(N))(cap^(N))N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(V),(cap^(N))(cap^(N))N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(VI), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(C) is a transducing sequence or absent; X¹ is A, K, an acidicamino acid residue, or is absent; X² is A, I, L, or V; X³ is A, D, I, L,P, or V; X⁴ is A, E, I, Y, or a basic amino acid residue; X⁵ is A, I, L,or V; X⁶ is A, G, S, T, or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T,or an aromatic amino acid residue; X⁹ is A, K, or an acidic amino acidresidue; X¹⁰ is A, C, M, S, α-aminobutyric acid, or norvaline; X¹¹ is A,I, L, V, or is absent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C)is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, ora heterocycle; and each amino acid residue side chain is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (V). In someembodiments, the peptide is a peptide of Formula (VI). In someembodiments, the peptide is a peptide of either Formula (V) or Formula(VI).

In some embodiments, the invention provides a compound for use in thetreatment of noise-induced hearing loss, wherein the compound is apeptide comprising: IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227);LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287);RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO: 305), wherein each terminusand each amino acid residue side chain of the peptide is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; 379; 380; and 381-396. In some embodiments, the peptideis a peptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396. Insome embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130. In some embodiments, the peptide is a peptide of any one of SEQID NOS: 187-316. In some embodiments, the peptide is a peptide of anyone of SEQ ID NOS: 381-396. In some embodiments, the peptide is SEQ IDNO: 379. In some embodiments, the peptide is SEQ ID NO: 380. In someembodiments, the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a compound for use in thetreatment of age-related hearing loss, wherein the compound is a peptideof Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (I). In someembodiments, the peptide is a peptide of Formula (II). In someembodiments, the peptide is a peptide of either Formula (I) or Formula(II).

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; 363-369; and 378. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 131-175; 177-186;317-361; and 363-368. In some embodiments, the peptide is a peptide ofany one of SEQ ID NOS: 131-175. In some embodiments, the peptide is apeptide of any one of SEQ ID NOS: 177-186. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 317-361. In someembodiments, the peptide is a peptide of any one of SEQ ID NOS: 363-369and 378. In some embodiments, the peptide is SEQ ID NO: 369. In someembodiments, the peptide is SEQ ID NO: 378. In some embodiments, thepeptide is not SEQ ID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a compound for use in thetreatment of age-related hearing loss, wherein the compound is a peptideof Formula (III) or Formula (IV),(cap^(N))(cap^(N))N-tran^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(III),(cap^(N))(cap^(N))N-tran^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(IV), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; X¹ is A, K, an acidic amino acid residue, or is absent; X² is A,I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I, Y, or a basicamino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T, or Y; X⁷ isA, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic amino acid residue;X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C, M, S,α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or is absent; X¹²is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy, aryloxy,arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and eachamino acid residue side chain is independently optionally capped with acapping group, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is a peptide of Formula (III). In someembodiments, the peptide is a peptide of Formula (IV). In someembodiments, the peptide is a peptide of either Formula (III) or Formula(IV).

In some embodiments, the invention provides a compound for use in thetreatment of age-related hearing loss, wherein the compound is a peptideof Formula (V) or Formula (VI),(cap^(N))(cap^(N))N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(V),(cap^(N))(cap^(N))N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(VI), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(C) is a transducing sequence or absent; X¹ is A, K, an acidicamino acid residue, or is absent; X² is A, I, L, or V; X³ is A, D, I, L,P, or V; X⁴ is A, E, I, Y, or a basic amino acid residue; X⁵ is A, I, L,or V; X⁶ is A, G, S, T, or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T,or an aromatic amino acid residue; X⁹ is A, K, or an acidic amino acidresidue; X¹⁰ is A, C, M, S, α-aminobutyric acid, or norvaline; X¹¹ is A,I, L, V, or is absent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C)is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, ora heterocycle; and each amino acid residue side chain is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (V). In someembodiments, the peptide is a peptide of Formula (VI). In someembodiments, the peptide is a peptide of either Formula (V) or Formula(VI).

In some embodiments, the invention provides a compound for use in thetreatment of age-related hearing loss, wherein the compound is a peptidecomprising: IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQID NO: 252); EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQID NO: 304); or EEYFM (SEQ ID NO: 305), wherein each terminus and eachamino acid residue side chain of the peptide is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; 379; 380; and 381-396. In some embodiments, the peptideis a peptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396. Insome embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130. In some embodiments, the peptide is a peptide of any one of SEQID NOS: 187-316. In some embodiments, the peptide is a peptide of anyone of SEQ ID NOS: 381-396. In some embodiments, the peptide is SEQ IDNO: 379. In some embodiments, the peptide is SEQ ID NO: 380. In someembodiments, the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a compound for use in theimprovement of normal hearing, wherein the compound is a peptide ofFormula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (I). In someembodiments, the peptide is a peptide of Formula (II). In someembodiments, the peptide is a peptide of either Formula (I) or Formula(II).

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; 363-369; and 378. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 131-175; 177-186;317-361; and 363-368. In some embodiments, the peptide is a peptide ofany one of SEQ ID NOS: 131-175. In some embodiments, the peptide is apeptide of any one of SEQ ID NOS: 177-186. In some embodiments, thepeptide is a peptide of any one of SEQ ID NOS: 317-361. In someembodiments, the peptide is a peptide of any one of SEQ ID NOS: 363-369and 378. In some embodiments, the peptide is SEQ ID NO: 369. In someembodiments, the peptide is SEQ ID NO: 378. In some embodiments, thepeptide is not SEQ ID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a compound for use in theimprovement of normal hearing, wherein the compound is a peptide ofFormula (III) or Formula (IV),(cap^(N))(cap^(N))N-tran^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(III),(cap^(N))(cap^(N))N-tran^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(IV), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; X¹ is A, K, an acidic amino acid residue, or is absent; X² is A,I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I, Y, or a basicamino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T, or Y; X⁷ isA, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic amino acid residue;X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C, M, S,α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or is absent; X¹²is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy, aryloxy,arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and eachamino acid residue side chain is independently optionally capped with acapping group, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is a peptide of Formula (III). In someembodiments, the peptide is a peptide of Formula (IV). In someembodiments, the peptide is a peptide of either Formula (III) or Formula(IV).

In some embodiments, the invention provides a compound for use in theimprovement of normal hearing, wherein the compound is a peptide ofFormula (V) or Formula (VI),(cap^(N))(cap^(N))N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-tran^(C)-C(O)-cap^(C)  Formula(V),(cap^(N))(cap^(N))N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-tran^(C)-C(O)-cap^(C)  Formula(VI), wherein

each cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(C) is a transducing sequence or absent; X¹ is A, K, an acidicamino acid residue, or is absent; X² is A, I, L, or V; X³ is A, D, I, L,P, or V; X⁴ is A, E, I, Y, or a basic amino acid residue; X⁵ is A, I, L,or V; X⁶ is A, G, S, T, or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T,or an aromatic amino acid residue; X⁹ is A, K, or an acidic amino acidresidue; X¹⁰ is A C, M, S, α-aminobutyric acid, or norvaline; X¹¹ is A,I, L, V, or is absent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C)is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, ora heterocycle; and each amino acid residue side chain is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof.

In some embodiments, the peptide is a peptide of Formula (V). In someembodiments, the peptide is a peptide of Formula (VI). In someembodiments, the peptide is a peptide of either Formula (V) or Formula(VI).

In some embodiments, the invention provides a compound for use in theimprovement of normal hearing, wherein the compound is a peptidecomprising: IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQID NO: 252); EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQID NO: 304); or EEYFM (SEQ ID NO: 305), wherein each terminus and eachamino acid residue side chain of the peptide is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; 379; 380; and 381-396. In some embodiments, the peptideis a peptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396. Insome embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130. In some embodiments, the peptide is a peptide of any one of SEQID NOS: 187-316. In some embodiments, the peptide is a peptide of anyone of SEQ ID NOS: 381-396. In some embodiments, the peptide is SEQ IDNO: 379. In some embodiments, the peptide is SEQ ID NO: 380. In someembodiments, the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of any one of SEQ ID NOs:1-369 and 378-396 to a subject in need or want thereof, or astereoisomer or pharmaceutically-acceptable salt thereof. In someembodiments, the peptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of any one of SEQ ID NOs:1-369 and 378-396 to a subject in need or want thereof, or apharmaceutically-acceptable salt thereof. In some embodiments, thepeptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of any one of SEQ ID NOs:1-369 and 378-396 to a subject in need or want thereof, or astereoisomer or pharmaceutically-acceptable salt thereof. In someembodiments, the peptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of any one of SEQ ID NOs:1-369 and 378-396 to a subject in need or want thereof, or apharmaceutically-acceptable salt thereof. In some embodiments, thepeptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a method of improving normalhearing, the method comprising administering a therapeutically-effectiveamount of a peptide of any one of SEQ ID NOs: 1-369 and 378-396 to asubject in need or want thereof, or a stereoisomer orpharmaceutically-acceptable salt thereof. In some embodiments, thepeptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a method of improving normalhearing, the method comprising administering a therapeutically-effectiveamount of a peptide of any one of SEQ ID NOs: 1-369 and 378-396 to asubject in need or want thereof, or a pharmaceutically-acceptable saltthereof. In some embodiments, the peptide is not any one of SEQ ID NOs:369 and 378-380.

In some embodiments, the invention provides a use of a peptide in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the peptide is a peptide of any one of SEQ ID NOs: 1-369and 378-396, or a stereoisomer or pharmaceutically-acceptable saltthereof. In some embodiments, the peptide is not any one of SEQ ID NOs:369 and 378-380.

In some embodiments, the invention provides a use of a peptide in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the peptide is a peptide of any one of SEQ ID NOs: 1-369and 378-396, or a pharmaceutically-acceptable salt thereof. In someembodiments, the peptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a use of a peptide in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the peptide is a peptide of any one of SEQ ID NOs: 1-369and 378-396, or a stereoisomer or pharmaceutically-acceptable saltthereof.

In some embodiments, the invention provides a use of a peptide in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the peptide is a peptide of any one of SEQ ID NOs: 1-369and 378-396, or a pharmaceutically-acceptable salt thereof. In someembodiments, the peptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a use of a peptide in thepreparation of a medicament for the improvement of normal hearing,wherein the peptide is a peptide of any one of SEQ ID NOs: 1-369 and378-396, or a stereoisomer or pharmaceutically-acceptable salt thereof.In some embodiments, the peptide is not any one of SEQ ID NOs: 369 and378-380.

In some embodiments, the invention provides a use of a peptide in thepreparation of a medicament for the improvement of normal hearing,wherein the peptide is a peptide of any one of SEQ ID NOs: 1-369 and378-396, or a pharmaceutically-acceptable salt thereof. In someembodiments, the peptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a peptide for use in thetreatment of noise-induced hearing loss, wherein the peptide is apeptide of any one of SEQ ID NOs: 1-369 and 378-396, or a stereoisomeror pharmaceutically-acceptable salt thereof. In some embodiments, thepeptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a peptide for use in thetreatment of noise-induced hearing loss, wherein the peptide is apeptide of any one of SEQ ID NOs: 1-369 and 378-396, or apharmaceutically-acceptable salt thereof. In some embodiments, thepeptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a peptide for use in thetreatment of age-related hearing loss, wherein the peptide is a peptideof any one of SEQ ID NOs: 1-369 and 378-396, or a stereoisomer orpharmaceutically-acceptable salt thereof. In some embodiments, thepeptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a peptide for use in thetreatment of age-related hearing loss, wherein the peptide is a peptideof any one of SEQ ID NOs: 1-369 and 378-396, or apharmaceutically-acceptable salt thereof. In some embodiments, thepeptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a peptide for use in theimprovement of normal hearing, wherein the peptide is a peptide of anyone of SEQ ID NOs: 1-369 and 378-396, or a stereoisomer orpharmaceutically-acceptable salt thereof. In some embodiments, thepeptide is not any one of SEQ ID NOs: 369 and 378-380.

In some embodiments, the invention provides a peptide for use in theimprovement of normal hearing, wherein the peptide is a peptide of anyone of SEQ ID NOs: 1-369 and 378-396, or a pharmaceutically-acceptablesalt thereof. In some embodiments, the peptide is not any one of SEQ IDNOs: 369 and 378-380.

The invention provides the use of pharmaceutically-acceptable salts ofany peptide described herein. Pharmaceutically-acceptable salts include,for example, acid-addition salts and base-addition salts. The acid thatis added to the peptide to form an acid-addition salt can be an organicacid or an inorganic acid. A base that is added to the peptide to form abase-addition salt can be an organic base or an inorganic base. In someembodiments, a pharmaceutically-acceptable salt is a metal salt. In someembodiments, a pharmaceutically-acceptable salt is an ammonium salt.

Metal salts can arise from the addition of an inorganic base to apeptide of the invention. The inorganic base consists of a metal cationpaired with a basic couterion, such as, for example, hydroxide,carbonate, bicarbonate, or phosphate. The metal can be an alkali metal,alkaline earth metal, transition metal, or main group metal. In someembodiments, the metal is lithium, sodium, potassium, cesium, cerium,magnesium, manganese, iron, calcium, strontium, cobalt, titanium,aluminum, copper, cadmium, or zinc.

In some embodiments, a metal salt is a lithium salt, a sodium salt, apotassium salt, a cesium salt, a cerium salt, a magnesium salt, amanganese salt, a iron salt, a calcium salt, a strontium salt, a cobaltsalt, a titanium salt, a aluminum salt, a copper salt, a cadmium salt,or a zinc salt.

Ammonium salts can arise from the addition of ammonia or an organicamine to a peptide of the invention. In some embodiments, the organicamine is triethyl amine, diisopropyl amine, ethanol amine, diethanolamine, triethanol amine, morpholine, N-methylmorpholine, piperidine,N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine,pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.

In some embodiments, an ammonium salt is a triethyl amine salt, adiisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, atriethanol amine salt, a morpholine salt, an N-methylmorpholine salt, apiperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt,a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazolesalt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or apipyrazine salt.

Acid addition salts can arise from the addition of an acid to a peptideof the invention. In some embodiments, the acid is organic. In someembodiments, the acid is inorganic. In some embodiments, the acid ishydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbicacid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid,formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid,propionic acid, butyric acid, fumaric acid, succinic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

In some embodiments, the salt is a hydrochloride salt, a hydrobromidesalt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfatesalt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactatesalt, a salicylate salt, a tartrate salt, an ascorbate salt, agentisinate salt, a gluconate salt, a glucaronate salt, a saccaratesalt, a formate salt, a benzoate salt, a glutamate salt, a pantothenatesalt, an acetate salt, a propionate salt, a butyrate salt, a fumaratesalt, a succinate salt, a methanesulfonate salt, an ethanesulfonatesalt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citratesalt, an oxalate salt, or a maleate salt.

In some embodiments, the invention provides an analogue of any peptidedisclosed herein, wherein the analogue possesses any number of aminoacid residues that are conservative substitutions of the amino acidresidues of the peptide disclosed herein.

In some embodiments, a peptide of any one of Formulae I, II, III, IV, V,and VI is a peptide of Table 1. In some embodiments, a peptide of anyone of Formulae I, II, III, IV, V, and VI is not a peptide of Table 1.In some embodiments, a peptide of any one of Formulae I, II, III, IV, V,and VI is not any one of SEQ ID NOS: 1-369 and 378-380. In someembodiments, a peptide of any one of Formulae I, III, and V is not SEQID NO: 369. In some embodiments, a peptide of any one of Formulae I,III, and V is not SEQ ID NO: 378.

In some embodiments, a peptide comprising the amino acid sequence EEYFM(SEQ ID NO: 305) is not SEQ ID NO: 379. In some embodiments, a peptidecomprising the amino acid sequence EEYFM (SEQ ID NO: 305) is not SEQ IDNO: 380.

Administration

A pharmaceutical composition containing a peptide can be administered topatients along with pharmaceutical excipients or diluents. Non-limitingexamples of suitable pharmaceutical excipients or diluents includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, magnesium carbonate, magnesium stearate, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol, buffered water, phosphate bufferedsaline and the like. These compositions can take the form of drops,solutions, suspensions, tablets, pills, capsules, powders,sustained-release formulations and the like. In some embodiments, thecomposition is an ear drop. In another preferred embodiment thecomposition containing a peptide in any form could be further modulatedusing suitable excipients and diluents including lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, water syrup, methylcellulose, methyl and propylhydroxybenzoates, talc, magnesium stearateand mineral oil. The formulations can additionally include lubricatingagents, wetting agents, emulsifying and suspending agents, preservingagents, sweetening agents or flavoring agents. The compositions can beformulated in a unit dosage form, each dosage containing, for example,from about 1 ng to 1000 mg of the peptide. In some embodiments, a dosecontains from 100-1000 mg of the peptide. In some embodiments, a dosecontains from 100-500 mg of the peptide. In some embodiments, a dosecontains from 200-300 mg of the peptide The term, “unit dosage form,”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticaldiluents or excipients. These may be administered to humans, domesticpets, livestock, or other animals with a pharmaceutically-acceptablediluents or excipients, in unit dosage form. Administration may betopical, intraaural, parenteral, intravenous, intra-arterial,subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic,intraventricular, intracapsular, intraspinal, intracisternal,intraperitoneal, intranasal, aerosol, by suppositories, or oraladministration. Formulations for oral use include tablets containing theactive ingredient(s) in a mixture with non-toxicpharmaceutically-acceptable excipients. These excipients may be, forexample, inert diluents or fillers (e.g., sucrose and sorbitol),lubricating agents, glidants, and antiadhesives (e.g., magnesiumstearate, zinc stearate, stearic acid, silicas, hydrogenated vegetableoils, or talc).

The active therapeutic formulation of the invention can be provided inlyophilized form for reconstituting, for instance, in isotonic, aqueous,or saline buffers for parental, subcutaneous, intradermal,intramuscular, or intravenous administration. The subject composition ofthe invention may also be administered to the patient in need of atherapeutic peptide by liquid preparations for orifice, e.g. oral,intraaural, nasal, or sublingual, administration such as suspensions,syrups or elixirs. The subject composition of the invention may also beprepared for oral administration such as capsules, tablets, pills, andthe like, as well as chewable solid formulations. The subjectcomposition of the invention may also be prepared as a cream for dermaladministration such as liquid, viscous liquid, paste, or powder. Thesubject composition of the invention may also be prepared as powder forlung administration with or without aerosolizing component. Thecomposition of the invention can be prepared as a drop, for example, anear drop.

The presently disclosed compositions can be used for delivery in oral,intraaural, intranasal, sublingual, intraduodenal, subcutaneous, buccal,intracolonic, rectal, vaginal, mucosal, pulmonary, transdermal,intradermal, parenteral, intravenous, intramuscular and ocular forms aswell as being able to traverse the blood-brain barrier.

Dosages

The dosage of any peptide of the present invention will vary dependingon the symptoms, age and body weight of the patient, the nature andseverity of the disorder to be treated or prevented, the route ofadministration, and the form of the composition. Any of the subjectformulations may be administered in a single dose or in divided doses.Dosages for the peptides of the present invention may be readilydetermined by techniques known to those of skill in the art or as taughtherein. Also, the present invention contemplates mixtures of more thanone subject peptide, as well as other therapeutic agents.

In certain embodiments, the dosage of the subject peptide will generallybe in the range of about 0.01 ng to about 10 g per kg body weight,specifically in the range of about 1 ng to about 0.1 g per kg, and morespecifically in the range of about 100 ng to about 10 mg per kg.

An effective dose or amount, and any possible affects on the timing ofadministration of the formulation, may need to be identified for anyparticular peptide of the present invention. This end may beaccomplished by routine experiment as described herein, using one ormore groups of animals, or in human trials if appropriate. Theeffectiveness of any peptide and method of treatment or prevention maybe assessed by administering the supplement and assessing the effect ofthe administration by measuring one or more indices associated with theneoplasm of interest, and comparing the post-treatment values of theseindices to the values of the same indices prior to treatment.

The precise time of administration and amount of any particular peptidethat will yield the most effective treatment in a given patient willdepend upon the activity, pharmacokinetics, and bioavailability of aparticular peptide, physiological condition of the patient (includingage, sex, disease type and stage, general physical condition,responsiveness to a given dosage and type of medication), route ofadministration, and the like. The guidelines presented herein may beused to optimize the treatment, e.g., determining the optimum timeand/or amount of administration, which will require no more than routineexperimentation consisting of monitoring the subject and adjusting thedosage and/or timing.

While the subject is being treated, the health of the subject may bemonitored by measuring one or more of the relevant indices atpredetermined times during a 24-hour period. Treatment, includingsupplement, amounts, times of administration and formulation, may beoptimized according to the results of such monitoring. The patient maybe periodically reevaluated to determine the extent of improvement bymeasuring the same parameters, the first such reevaluation typicallyoccurring at the end of four weeks from the onset of therapy, andsubsequent reevaluations occurring every four to eight weeks duringtherapy and then every three months thereafter. Therapy may continue forseveral months or even years, with a minimum of one month being atypical length of therapy for humans. Adjustments to the amount(s) ofpeptide administered and possibly to the time of administration may bemade based on these reevaluations.

Treatment may be initiated with smaller dosages which are less than theoptimum dose of the peptide. Thereafter, the dosage may be increased bysmall increments until the optimum therapeutic effect is attained.

The combined use of several peptides of the present invention, oralternatively other peptides, may reduce the required dosage for anyindividual component because the onset and duration of effect of thedifferent components may be complimentary. In such combined therapy, thedifferent peptides may be delivered together or separately, andsimultaneously or at different times within the day.

Toxicity and therapeutic efficacy of subject peptides may be determinedby standard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD₅₀ and the ED₅₀. Although peptidesthat exhibit toxic side effects may be used, care should be taken todesign a delivery system that targets the peptides to the desired sitein order to reduce side effects.

The data obtained from cell culture assays and animal studies may beused in formulating a range of dosage for use in humans. The dosage ofany supplement, or alternatively of any components therein, liespreferably within a range of circulating concentrations that include theED₅₀, with little or no toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized. For peptides of the present invention, the therapeuticallyeffective dose may be estimated initially from cell culture assays. Adose may be formulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test peptide which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information may be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography (HPLC).

Formulations

The peptide-based compositions of the present invention may beadministered by various means, depending on their intended use, as iswell known in the art. For example, if compositions of the presentinvention are to be administered orally, they may be formulated astablets, capsules, granules, powders or syrups. Alternatively,formulations of the present invention may be administered parenterallyas injections (intravenous, intramuscular or subcutaneous), dropinfusion preparations or suppositories. The peptide-based compositionscan also be administered into deep lung by aerosolizing the compositioninto 1-5 um particle using standard techniques known in the art eitherwith or without addition of aerosolizing excipient. For application bythe ophthalmic mucous membrane route, compositions of the presentinvention may be formulated as eye drops or eye ointments. Auralpharmaceutical compositions can be formulated as ear drops, ointments,creams, liquids, gels, or salves for application to the ear, eitherinternally or superficially. These formulations may be prepared byconventional means, and, if desired, the compositions may be mixed withany conventional additive, such as an excipient, a binder, adisintegrating agent, a lubricant, a solubilizing agent, a suspensionaid, an emulsifying agent or a coating agent.

In formulations of the subject invention, wetting agents, emulsifiersand lubricants, such as sodium lauryl sulfate and magnesium stearate, aswell as coloring agents, release agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants may bepresent in the formulated agents.

Subject peptide-based compositions may be suitable for oral,intra-aural, nasal, topical (including buccal and sublingual), rectal,vaginal, aerosol and/or parenteral administration. The formulations ofthe peptide-based compositions may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amounts of composition that may be combined with otherexcipients to produce a single dose may vary depending upon the subjectbeing treated, and the particular mode of administration.

Formulations suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis,usually sucrose and acacia or tragacanth), powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia), each containing a predetermined amount of a subjectcomposition thereof as an active ingredient. Compositions of the presentinvention may also be administered as a bolus, electuary, or paste.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject peptidecomposition is mixed with one or more pharmaceutically-acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such ascarboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as acetyl alcohol and glycerol monostearate; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and mixtures thereof; and (10) coloring agents. In the case ofcapsules, tablets and pills, the peptide compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the subject compositionmoistened with an inert liquid diluent. Tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art.

Liquid dosage forms for oral administration includepharmaceutically-acceptable emulsions, microemulsions, gels, solutions,suspensions, syrups and elixirs. The liquid dosage peptide formulationmay contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, germ, olive,castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspension dosage of the peptide formulation may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

The peptide formulations for rectal or vaginal administration may bepresented as a suppository, which may be prepared by mixing a peptidewith one or more suitable carriers and other excipients comprising, forexample, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the body cavity and releasepeptide. Formulations which are suitable for vaginal administration alsoinclude pessaries, tampons, creams, gels, pastes, foams or sprayformulations containing excipients as are known in the art to beappropriate.

The peptide dosage formulations for transdermal administration of asubject composition includes drops, powders, sprays, ointments, pastes,creams, lotions, gels, solutions, patches and inhalants. The activecomponent may be mixed under sterile conditions with apharmaceutically-acceptable carrier, and with any preservatives,buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to asubject composition, excipients, such as animal and vegetable fats,oils, waxes, paraffin, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonite, silicic acid, talc and zincoxide, or mixtures thereof. The peptide compositions of the presentinvention may also be in the form of baby wipes.

Powders and sprays may contain, in addition to a subject composition,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays may additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

The peptide compositions of the present invention may alternatively beadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. A non-aqueous (e.g., fluorocarbon propellant) suspension couldbe used. Sonic nebulizers may be used because they minimize exposing thepeptide to shear, which may result in degradation of the peptidescontained in the subject compositions.

Ordinarily, an aqueous aerosol is made by formulating an aqueoussolution or suspension of a subject composition together withconventional pharmaceutically-acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularsubject composition, but typically include non-ionic surfactants(Tweens, Pluronics, or polyethylene glycol), innocuous proteins likeserum albumin, sorbitan esters, oleic acid, lecithin, amino acids suchas glycine, buffers, salts, sugars or sugar alcohols. Aerosols generallyare prepared from isotonic solutions.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise a subject composition in combination with one ormore pharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity may be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of Formula (I) or Formula(II) to a subject in need or want thereof,(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of Formula (I) or Formula(II) to a subject in need or want thereof,(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a method of improving normalhearing, the method comprising administering a therapeutically-effectiveamount of a peptide of Formula (I) or Formula (II) to a subject in needor want thereof,(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

In some embodiments, the peptide is a peptide of Formula (I).

In some embodiments, X¹ is A, D, E, K or is absent; X⁴ is A, E, H, I, K,R, or Y; X⁸ is A, F, P, S, T, W, or Y; and X⁹ is A, D, E, or K.

In some embodiments, cap^(N) is H and cap^(C) is OH.

In some embodiments, at least one amino acid residue of the peptidepossesses the D-configuration.

In some embodiments, at least one of amino acid residues X¹⁻¹¹ possessesthe D-configuration.

In some embodiments, pep^(N), pep^(C), and tran^(N) are absent, andtran^(C) is a transducing sequence.

In some embodiments, the transducing sequence is a poly-argininesequence.

In some embodiments, the poly-arginine sequence consists of about ninearginine residues.

In some embodiments, at least one arginine residue of the poly-argininesequence possesses the D-configuration.

In some embodiments, each residue of the poly-arginine sequencepossesses the D-configuration.

In some embodiments, the peptide is administered orally, topically,intraaurally, parenterally, intravenously, intra-arterially,subcutaneously, intramuscularly, intracranially, or intranasally.

In some embodiments, the peptide is administered topically.

In some embodiments, the peptide is administered to the skin, hair,outer ear, tympanic membrane, buccal cavity, nasal cavity, or sublingualcavity.

In some embodiments, the peptide is administered to the tympanicmembrane.

In some embodiments, the peptide is administered in the form of a drop.

In some embodiments, the subject is a human.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:131-175; 177-186; 317-361; and 363-368.

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide to a subject in need orwant thereof, wherein the peptide comprises: IGLCA (SEQ ID NO: 207);YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276);YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO:305), wherein each terminus and each amino acid residue side chain ofthe peptide is independently optionally capped with a capping group, ora stereoisomer or pharmaceutically-acceptable salt of any of theforegoing, wherein the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide to a subject in need orwant thereof, wherein the peptide comprises: IGLCA (SEQ ID NO: 207);YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276);YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO:305), wherein each terminus and each amino acid residue side chain ofthe peptide is independently optionally capped with a capping group, ora stereoisomer or pharmaceutically-acceptable salt of any of theforegoing, wherein the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a method of improving normalhearing, the method comprising administering a therapeutically-effectiveamount of a peptide to a subject in need or want thereof, wherein thepeptide comprises: IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227); LFNEI(SEQ ID NO: 252); EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287); RIKYG(SEQ ID NO: 304); or EEYFM (SEQ ID NO: 305), wherein each terminus andeach amino acid residue side chain of the peptide is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing, wherein thepeptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the peptide comprises IGLCA (SEQ ID NO: 207).

In some embodiments, the peptide comprises YIKVQ (SEQ ID NO: 227).

In some embodiments, the peptide comprises LFNEI (SEQ ID NO: 252).

In some embodiments, the peptide comprises EMFTI (SEQ ID NO: 276).

In some embodiments, the peptide comprises YRGLL (SEQ ID NO: 287).

In some embodiments, the peptide comprises RIKYG (SEQ ID NO: 304).

In some embodiments, the peptide comprises EEYFM (SEQ ID NO: 305).

In some embodiments, the peptide further comprises a transducingsequence.

In some embodiments, the transducing sequence is positioned at theC-terminus of the peptide.

In some embodiments, the transducing sequence is a poly-argininesequence.

In some embodiments, the poly-arginine sequence consists of about ninearginine residues.

In some embodiments, at least one amino acid residue of the peptidepossesses the D-configuration.

In some embodiments, at least one arginine residue of the poly-argininesequence possesses the D-configuration.

In some embodiments, each residue of the poly-arginine sequencepossesses the D-configuration.

In some embodiments, the peptide is administered orally, topically,intraaurally, parenterally, intravenously, intra-arterially,subcutaneously, intramuscularly, intracranially, or intranasally.

In some embodiments, the peptide is administered topically.

In some embodiments, the peptide is administered to the skin, hair,outer ear, tympanic membrane, buccal cavity, nasal cavity, or sublingualcavity.

In some embodiments, the peptide is administered to the tympanicmembrane.

In some embodiments, the peptide is administered in the form of a drop.

In some embodiments, the subject is a human.

In some embodiments, the peptide is a peptide of any one of SEQ ID NOS:1-130; 187-316; and 381-396.

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of any one of SEQ ID NOS:369 and 378-380, or a pharmaceutically-acceptable salt thereof, to asubject in need or want thereof.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the compound is a peptide of any one of SEQ ID NOS: 369and 378-380, or a pharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a compound for use in thetreatment of noise-induced hearing loss, wherein the compound is apeptide of any one of SEQ ID NOS: 369 and 378-380, or apharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of any one of SEQ ID NOS:369 and 378-380, or a pharmaceutically-acceptable salt thereof, to asubject in need or want thereof.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the compound is a peptide of any one of SEQ ID NOS: 369and 378-380, or a pharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a compound for use in thetreatment of age-related hearing loss, wherein the compound is a peptideof any one of SEQ ID NOS: 369 and 378-380, or apharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a method of improvinghearing, the method comprising administering a therapeutically-effectiveamount of a peptide of any one of SEQ ID NOS: 369 and 378-380, or apharmaceutically-acceptable salt thereof, to a subject in need or wantthereof.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the improvement of hearing, wherein thecompound is a peptide of any one of SEQ ID NOS: 369 and 378-380, or apharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a compound for use in theimprovement of hearing, wherein the compound is a peptide of any one ofSEQ ID NOS: 369 and 378-380, or a pharmaceutically-acceptable saltthereof.

In some embodiments, the peptide is administered orally, topically,intraaurally, parenterally, intravenously, intra-arterially,subcutaneously, intramuscularly, intracranially, or intranasally.

In some embodiments, the peptide is administered topically.

In some embodiments, the peptide is administered to the skin, hair,outer ear, tympanic membrane, buccal cavity, nasal cavity, or sublingualcavity.

In some embodiments, the peptide is administered to the tympanicmembrane.

In some embodiments, the peptide is administered in the form of a drop.

In some embodiments, the subject is a human.

EXAMPLES Example 1 Materials and Methods

Peptide of the natural configuration: Peptides were synthesized byMimotopes using their unique proprietary parallel array synthesisplatform. Each peptide contains an amino acid sequence of the inventionand optionally a 9-residue arginine cell transduction sequencepositioned at the C-terminus of the peptide to facilitate cellularuptake. The peptides are presented in Table 1.

Peptides with D-amino acid residues are synthesized as peptides withL-amino acid residues are synthesized. The D-amino acids with theappropriate protecting groups are commercially available for use onautomated systems to construct peptides. Peptides described herein canbe made entirely from L-amino acids, entirely from D-amino acids, orfrom a mixture of both in any proportion. A peptide is consideredstereochemically-mixed if the peptide comprises at least one L-, and atleast one D-amino acid residue. The transduction tag can similarly bemade entirely from L-amino acids, entirely from D-amino acids, or from amixture of both in any proportion. Peptides differing only instereochemistry may possess differing properties, benefits,specificities, affinities, and activities at the same or at differentreceptors. In some cases, peptides differing only in stereochemistry mayexhibit comparable specificities and activities.

Each peptide is constructed both with and without a FITC-label(Fluorescein isothiocyanate). FITC labeled peptides are used for FACSanalysis. The peptides lacking the FITC label are used for in vitroinhibition assays and in vivo treatment studies.

Reagents: Nuclease-resistant phosphorylated oligonucleotide waspurchased from Oligos Etc., Inc. The sequence was5′-TCCATGACGTTCCTGACGTT-3′ (SEQ ID NO: 377) (CpG-oligodeoxynucleotide(ODN)). TNF-α assays were performed using assay kits purchased from R&DSystems. Mouse IL-1α and TNF-α were purchased from R&D Systems. PMA(phorbol myristate acetate) and LPS (Lipopolysaccaride) were purchasedfrom Sigma. The TLR ligands flagellin, zymosan, and Poly (I:C) werepurchased from Invivogen. Cytokine assays were performed using assaykits purchased from R&D Systems. (Heat-inactivated S. pneumoniae was thekind gift of Dr. Thomas DeMaria, The Ohio State University College ofMedicine, Department of Otolaryngology, Columbus, Ohio.)

Cell lines and cultures: RAW264.7 (murine monocyte/macrophage cells(American Type Culture Collection) were cultured at 37° C. in a 5% CO₂humidified incubator and grown in DMEM (Invitrogen Life Technologies)supplemented with 10% (v/v) heat-inactivated FCS, 1.5 mM L-glutamine,100 U/ml penicillin, and 100 μg/ml streptomycin.

Cytokine secretion: RAW264.7 cells were plated at 1.5×10⁵cells/well-3×10⁵ cells/well in 48-well plates. After 24 hours, the cellswere incubated with peptides at various concentrations at roomtemperature in triplicate either before, simultaneous with, or afteractivation with various PAMPs for 18 hours. Cell-free supernatants wereanalyzed for cytokines by ELISA, in quadruplicate. RAW264.7 cells werestimulated with either CpG-ODN (1 μg/ml or 1.25 μg/ml), LPS (about 1ng/ml), Poly (I:C) (about 10 μg/ml), flagellin (about 5 ng/ml), orzymosan (about 10 μg/ml). Dose response curves were done with each PAMPto determine optimal stimulation concentration. For CpG-ODN stimulation,cells were incubated for 4 hours at 37° C., supernatants collected, andTNF-α measured by ELISA. Any cytokine involved in inflammatory diseasemediated toll receptor signaling can be measured using similar assays.

Flow Cytometry: Cells are analyzed by flow cytometry (FACScan, BectonDickinson) using Cellquest software to quantify internalization ofpeptides. Gates are drawn to exclude dead cells based on 7-AAD(7-amino-actinomycin D) staining. Flourescence due to cell-surfacebinding of FITC-labeled peptides is quenched using trypan blue. Dataobtained are geometric mean fluorescent units (F) with backgroundautofluorescence subtracted.

Immunoblotting: RAW264.7 cells (6×10⁵) are plated in 12 well platesovernight. Cells are incubated for 15 minutes at room temperature withpeptides to be tested or control scrambled peptides, and then stimulatedwith medium or LPS (1 ng/ml) for either 15 or 30 minutes. Cells arelysed, and proteins fractionated by SDS/PAGE (Sodium DodecylSulfate/Polyacrylamide Gel Electrophoresis) (12%). Immunoblotting isdone using Phospho-IkB-α (Ser32) antibody (Cell Signaling), detectedusing horseradish peroxidase-conjugated secondary antibody, andvisualized by chemiluminescence. Measurements of band intensity are madeusing the Nucleo Tech Gel Expert software linked to an Epson expression636 scanner and expressed as intensity/area.

Cell viability: Cells were assayed for viability using CellTiter 96Aq_(ueous) One Solution Cell Proliferation Assay (Promega) followingmanufacturer's instructions. Briefly, cells were seeded in 96 wellplates and incubated overnight at 37° C. in a humidified 5% CO₂atmosphere. When samples were ready to be assayed, 20 μl of reagent wasadded into each well, and incubated for 1.5 hrs at 37° C. in ahumidified 5% CO₂ atmosphere. Absorbances were read at 490 nm using anELx800 absorbance microplate reader (BioTek) and data analyzed with Gen5software (BioTek). Some peptides were evaluated for their effect on cellviability by trypan blue exclusion staining over a range ofconcentrations and then each peptide was tested for cytokine inhibitionat the maximum concentration that had no effect on cell viability.

Example 2 Effect of Peptides on CpG-ODN-Induced Cytokine Secretion

The effect of several peptides on TNF-α secretion from RAW264.7 cells inresponse to stimulation by CpG-ODN was studied. Each peptide wasinitially tested at 3 concentrations, 37 μM, 22.2 and 11.1 μM. Seventeenpeptides demonstrating inhibition of TNF-α secretion of 50-100% acrossall three doses are presented (Table 2). The peptides were then testedat 11.1 μM, 7.4 μM, and 3.7 μM (Table 3). The peptides continued todemonstrate inhibitory activity at 7.4 μM, and twelve of the peptideshad inhibitory activity at 3.7 μM. Cell viability was examined for eachpeptide at the concentrations tested for TNF-α inhibition. No decreasein cell viability was demonstrated.

TABLE 2 Percent Inhibition of TNF-αsecretion by S1-S22 peptides with a R⁹ sequence(SEQ ID NOs: 42-44; 68-77; 79-81; 83; and 102-106). RAW264.7 cells were plated at3 ×10⁵ cells/well in 48-well plates. After 24 h the cells were incubated with peptideat various concentrations at room temperature in triplicate for 15 minutes andthen stimulated with 1 ug/ml Cpg-ODN. Cells were then incubated for 4 hoursat 37° C., supernatants collected, and TNF-α measured by ELISA. Percentinhibition was calculated by comparing TNF-a secretion from cells incubatedwith peptide to control cells with no peptide treatment. Peptide 37 μM22.2 μM 11.1 μM Sequence  42(S1)-R⁹   97  96 85EMFTILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 42)  43(S2)-R⁹ 100 94 91 MFTILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 43)  44(S3)-R⁹ 95  96 91 FTILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 44) 68(S4)-R⁹ 100 100 95EMFTILEEYFMYRGLLGLRIKYGRLFNRRRRRRRRR (SEQ ID NO: 68)  69(S5)-R⁹ 100 10093 EMFTILEEYFMYRGLLGLRIKYGRLFRRRRRRRRR (SEQ ID NO: 69)  70(S6)-R⁹ 100100 93 EMFTILEEYFMYRGLLGLRIKYGRLRRRRRRRRR (SEQ ID NO: 70)  71(S7)-R⁹  91 82 56 EMFTILEEYFMYRGLLGLRIKYGRRRRRRRRRR (SEQ ID NO: 71)  72(S8)-R⁹ 100100 92 EMFTILEEYFMYRGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 72)  73(S9)-R⁹ 100100 84 EMFTILEEYFMYRGLLGLRIKYRRRRRRRRR (SEQ ID NO: 73)  74(S10)-R⁹ 100100 91 EMFTILEEYFMYRGLLGLRIKRRRRRRRRR (SEQ ID NO: 74)  75(S11)-R⁹  98 97 92 EMFTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 75)  76(S12)-R⁹  87  8482 EMFTILEEYFMYRGLLGLARRRRRRRRR (SEQ ID NO: 76)  77(S13)-R⁹  93  89 84EMFTILEEYFMYRGLLGLRRRRRRRRR (SEQ ID NO: 77)  79(S14)-R⁹  97  93 85EMFTILEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 79)  80(S15)-R⁹  91  87 78EMFTILEEYFMYRGLRRRRRRRRR (SEQ ID NO: 80)  81(S16)-R⁹  90  86 84EMFTILEEYFMYRGRRRRRRRRR (SEQ ID NO: 81)  83(S17)-R⁹  89  82 72EMFTILEEYFMYRRRRRRRRR (SEQ ID NO: 83) 102(S18)-R⁹ —  91 72MFTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 102) 103(S19)-R⁹ —  99 93FTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 103) 104(S20)-R⁹ —  93 74TILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 104) 105(S21)-R9 —  91 62ILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 105) 106(S22)-R⁹ —  92 70LEEYFMYGLLGLRIRRRRRRRRR (SEQ ID NO: 106)

TABLE 3 Inhibition of TNF-αsecretion by S1-S22 peptides with an R⁹ sequence (SEQ IDNOs: 42-44; 68-77; 79-81; 83; and 102-106). RAW264.7 cells were plated at 3X10⁵cells/well in 48-well plates. After 24 h the cells were incubated with peptide at variousconcentrations at room temperature in triplicate for 15 minutes and then stimulated with1 ug/ml Cpg-ODN. Cells were then incubated for 4 hours at 37°C., supernatants collected,and TNF-a measured by ELISA. Percent inhibition was calculated by comparing TNF-αsecretion from cells incubated with peptide to control cells with no peptide treatment.Peptide 11 μM 7 μM 3.1 μM Sequence  42(S1)-R⁹ 83 67 37EMFTILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 42)  43(S2)-R⁹ 70 51 0 MFTILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 43)  44(S3)-R⁹ 7824  0 FTILEEYFMYRGLLGLRIKYGRLFNEIRRRRRRRRR (SEQ ID NO: 44)  68(S4)-R⁹ 9583 69 EMFTILEEYFMYRGLLGLRIKYGRLFNRRRRRRRRR (SEQ ID NO: 68)  69(S5)-R⁹ 9394 66 EMFTILEEYFMYRGLLGLRIKYGRLFRRRRRRRRR (SEQ ID NO: 69)  70(S6)-R⁹ 9487 63 EMFTILEEYFMYRGLLGLRIKYGRLRRRRRRRRR (SEQ ID NO: 70)  71(S7)-R⁹ 3829 21 EMFTILEEYFMYRGLLGLRIKYGRRRRRRRRRR (SEQ ID NO: 71)  72(S8)-R⁹ 93 8043 EMFTILEEYFMYRGLLGLRIKYGRRRRRRRRR (SEQ ID NO: 72)  73(S9)-R⁹ 85 76  3EMFTILEEYFMYRGLLGLRIKYRRRRRRRRR (SEQ ID NO: 73)  74(S10)-R⁹ 92 80 35EMFTILEEYFMYRGLLGLRIKRRRRRRRRR (SEQ ID NO: 74)  75(S11)-R⁹ 93 84 31EMFTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 75)  76(S12)-R⁹ 84 67 44EMF'TILEEYFMYRGLLGLRRRRRRRRRR (SEQ ID NO: 76)  77(S13)-R⁹ 81 77 18EMFTILEEYFMYRGLLGLRRRRRRRRR (SEQ ID NO: 77)  79(S14)-R⁹ 86 77  0EMFTILEEYFMYRGLLRRRRRRRRR (SEQ ID NO: 79)  80(S15)-R⁹ 81 68 57EMFTILEEYFMYRGLRRRRRRRRR (SEQ ID NO: 80)  81(S16)-R⁹ 70 53 26EMFTILEEYFMYRGRRRRRRRRR (SEQ ID NO: 81)  83(S17)-R⁹ 57 44  0EMFTILEEYFMYRRRRRRRRR (SEQ ID NO: 83) 102(S18)-R⁹ 72 48 —MFTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 102) 103(S19)-R⁹ 93 87 —FTILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 103) 104(S20)-R⁹ 74 60 —TILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 104) 105(S21)-R⁹ 62 52 —ILEEYFMYRGLLGLRIRRRRRRRRR (SEQ ID NO: 105) 106(S22)-R⁹ 70 53 —LEEYFMYGLLGLRIRRRRRRRRR (SEQ ID NO: 106)

Example 3 Effect of Peptides on of CpG-ODN-Induced Cytokine Secretion

Inhibition of TNF-α secretion by various T-peptides was examined.RAW264.7 cells were plated at 3×10⁵ cells/well in 48-well plates. After24 h the cells were incubated with peptide at various concentrations atroom temperature in triplicate for 15 minutes and then stimulated with1.25 ug/ml CpG-ODN or 1 ng/ml LPS. Cells were then incubated for 4 hoursat 37° C., supernatants collected, and TNF-α measured by ELISA. Percentinhibition was calculated by comparing TNF-α secretion from cellsincubated with peptide to control cells with no peptide treatment. Theinhibitive effects of peptides T3 (SEQ ID NO: 319), T11 (SEQ ID NO:327), T21 (SEQ ID NO: 337), T36 (SEQ ID NO: 352), T37 (SEQ ID NO: 353),T51 (SEQ ID NO: 367), and T52 (SEQ ID NO: 368) were compared toinhibition by an analogue of P13 (SEQ ID NO: 369) having a sequence ofnine arginine residues at the C-terminus (P13-R⁹ (SEQ ID NO: 378)).(Table 4).

TABLE 4 Percent Inhibition of TNF-αsecretion by T peptides. Percent inhibitionwas calculated by comparing TNF-a secretion from cells incubatedwith peptide to control cells with no peptide treatment. CpG stimulationPeptide 22 μM 11.1 μM 7.1 μM Sequence P13-R⁹ 86 65 32DIVKLTVYDCIRRRRRRRRR (SEQ ID NO: 378) T3-R⁹ 99 92 85AIVKLTVYDCIRRRRRRRRR (SEQ ID NO: 133) T21-R⁹ 98 90 69DIVKLYVYDCIRRRRRRRRR (SEQ ID NO: 151) T36-R⁹ 82 70 50DIIKLTVYDCIRRRRRRRRR (SEQ ID NO: 166) T37-R⁹ 93 87 46DIVKVTVYDCIRRRRRRRRR (SEQ ID NO: 167) T51-R⁹ 99.7 98 94AIVKLTVYACIRRRRRRRRR (SEQ ID NO: 181) T52-R⁹ 100 99.2 97.8AIIKVYVYACIRRRRRRRRR (SEQ ID NO: 182) LPS Stimulation Peptide 22.2 μM11.1 μM 7.4 μM Sequence P13-R⁹ 69 13 0 DIVKLTVYDCIRRRRRRRRR(SEQ ID NO: 378) T3-R⁹ 77 65 33 AIVKLTVYDCIRRRRRRRRR (SEQ ID NO: 133)T11-R⁹ 91 81 68 DIVKLTVYACIRRRRRRRRR (SEQ ID NO: 141)

Example 4 Structure-Activity Testing of Peptides Derived from P13 (SEQID NO: 369)

Structure-activity relationships (SAR) were investigated to determinetolerances to residue modification in P13 (SEQ ID NO: 369). Peptidesused in the SAR include SEQ ID NOS: 131-182, used to study theactivities of SEQ ID NOS: 317-368. Peptides possessing the followingstructural modifications were made and evaluated for activity vis-à-visP13 (SEQ ID NO: 369):

1. Deletions of N- and/or C-terminal residues;

2. Alanine scan at each residue;

3. Comparison of residues with like charges at the same position (forexample, Asp or Glu at the same position; Lys, Arg, or His at the sameposition);

4. Comparison of hydroxylated side chains at the same position (forexample, Ser or Thr at the same position);

5. Comparison of aromatic side chains at the same position (for example,Phe, Tyr, His, or Trp at the same position);

6. Replacement of side chains with sulfur-containing side chains (forexample, Met and Cys);

7. Conservative replacement of branched aliphatic side chains (forexample, Leu, Ile, and Val);

8. Disruption of structure by inclusion of alternate residues;

9. Reverse and scrambled sequence; and

10. Dimerization.

The SAR revealed that certain substitutions led to peptides withactivity superior to that of P13 (SEQ ID NO: 369). The substitution of asingle amino acid, in at least five different cases, and thesubstitution of two or more amino acids in at least two cases, resultedin superior activity. These seven peptides are SEQ ID NOS: 133, 141,151, 166, 167, 181, and 182. The discovery was unexpected in that theactivity of the SAR derivatives was expected to be comparable or lesserthan that of P13 (SEQ ID NO: 369). Activity was defined as inhibition ofTNF-α after stimulation of RAW264.7 cells with CpG.

Example 5 Effect of Peptides on Otitis Media

Induction of Otitis Media:

BALB/c (Bagg albino) mice, about 8-12 weeks of age, are anesthetizedwith a subcutaneous injection of xylazine & ketamine (about 0.1 mg/30 gmbody weight) and their ears examined under the operating microscope toassure they are free of infection or perforation. One group of animalsis injected with PBS (Phospho-buffered saline) in one ear and with about10 μM of a peptide of Table 1 in the opposite ear, to determine theeffect of peptide without added bacteria. A second group of animalsreceive about 5.0 μl of PBS plus heat-inactivated S. pneumoniae (about10⁹ CFU/ml) in one ear and about 5.0 μl of peptide (about 10 μM) plusheat-inactivated S. pneumoniae (about 10⁹ CFU/ml) in the opposite ear.Injections are done through the tympanic membrane. Animals are killedabout 3 days after bacterial injection and tissue is histologicallyprocessed to assess middle ear disease. Inflammation is quantified bymeasuring 1) area of fluid present in the middle ear; 2) number of cellsin middle ear fluid; and 3) thickness of the tympanic membrane (TM)taken at a point away from the injection site. Data are obtained frommice (n=18) injected with PBS alone for each of the histologicalparameters measured, to serve as a control group. Disease induction isdefined as positive if the ear injected with S. pneumoniae withoutpeptide demonstrated an increase of at least two standard deviationsabove the control PBS treated mice in at least two of the threeparameters assessed for middle ear inflammation: Fluid area, cellnumber, thickness of the tympanic membrane.

Tissue Collection:

At the end of the experimental treatment, mice are killed and tissuescollected for histology. Mice are overdosed on anesthetic and perfusedintracardially with about 1.0 mL of saline, followed by about 20 mL offixative (about 1.5% paraformaldehyde, about 3% glutaraldehyde in about0.1 M phosphate buffer). The middle ears are left intact and connectedto each other by the skull base so both ears are processed together forhistology and sectioning. This enables all histologic embedding,sectioning, staining, and analysis to be done on the two sidessimultaneously to reduce any impact of processing variables on thesubsequent quantitative analyses. Middle ears are decalcified, embeddedin glycol methacrylate plastic, sectioned at about 5 μm, mountedserially on glass slides, stained, and coverslipped.

Histopathologic Analysis:

Three consecutive sections at the level of the umbo and promontory areselected for measures of 1) area of fluid present in the middle ear; 2)number of cells in middle ear fluid; and 3) thickness of the tympanicmembrane. Each measurement is taken on the three sequential sections perspecimen.

Statistical Analyses:

To determine the effect of peptide without added bacteria, animals areinjected in one ear with PBS alone, and the other ear with about 10 μMpeptide. Paired t-tests are done comparing the effect of PBS alone withthe effect of peptide for each of the three histological parameters: 1)area of fluid present in the middle ear; 2) number of cells in middleear fluid; and 3) thickness of the tympanic membrane. Paired t-tests aredone using these animals comparing the effect of peptide plus S.pneumoniae in one ear with S. pneumoniae alone in the opposite ear foreach of the histological parameters described above.

Example 6 Effect of Peptides on Septic Shock

Inhibition of inflammatory mediators in a murine septic shock model.BALB/c mice are injected i.p. with PBS, LPS at about 100 μg/mouse/250μl, or about 100 μg LPS plus various doses of peptides. Serum iscollected at about 2 and about 6 hours after treatment and evaluated forthe pro-inflammatory cytokines MIP-2 and TNF-α by ELISA, and for solubleICAM-1.

Example 7 Effects of P13 (SEQ ID NO: 369) on Mouse Middle Ear

Assay of Effects Caused by Peptide without Added Bacteria.

Five mice were injected in one ear with PBS and in the opposite ear with10 μM peptide P13 (SEQ ID NO: 369). Three days later the animals werekilled, and the middle ears embedded, sectioned, stained and evaluatedfor fluid area, infiltrating cell number, and thickness of the tympanicmembrane. Paired t-tests (2-tailed) were used to analyze each of thethree parameters. In the absence of bacterial-induced inflammation, nodifferences were seen between the PBS-injected ear and P13-injected earin 1) fluid area (p=0.104); 2) cell number (p=0.880); or 3) tympanicmembrane thickness (p=0.891).

Assay of Effects Caused by Peptide with Added Bacteria.

To examine the effectiveness of the peptide to affect inflammation invivo, twenty BALB/c mice were injected in the middle ear on one sidewith heat-inactivated S. pneumoniae plus PBS, and in the middle ear onthe opposite side with heat-inactivated S. pneumoniae plus 10 μM peptideP13 (SEQ ID NO: 369). Three days later the animals were killed, andevaluated for middle ear fluid area, infiltrating cell number, andthickness of the tympanic membrane. Disease development was defined asan increase over background controls (PBS injected ears n=18) of atleast two standard deviations in two out of the three parametersquantified. A total of 7 out of 20 mice met the criteria for diseaseinduction. Analysis of middle ears by paired t-tests from these 7 micewith disease showed that peptide treatment significantly reduced theamount of fluid (p=0.004), infiltrating cell number (p=0.02), andthickness of the tympanic membrane (p=0.002). Examination of these threeparameters of inflammation for each individual mouse with diseaseillustrated the dramatic effect seen with a single treatment of peptideP13 (SEQ ID NO: 369). Of interest, 6 of the 7 mice demonstratedreductions in all areas of inflammation, while one animal showed onlymodest reduction in fluid area and tympanic membrane thickness, and noreduction in cell number. Injection of heat-killed bacteria resulted ina marked inflammatory response in the middle ear after 3 days. This wascharacterized by mucosal and tympanic membrane swelling, cellularinfiltration, and significant fluid (effusion) secretion andaccumulation that filled the middle ear space. The inflammatory responseled to significant mucosal cellular hypertrophy and active secretion ofmucins and other fluids. When peptide P13 (SEQ ID NO: 369) was injectedwith the bacteria, a significant reduction was seen in fluidaccumulation into the middle ear space and reduced mucosal hypertrophy.

TABLE 5 Peptide Inhibition of Middle Ear Inflammation^(a) TympanicMembrane Fluid Area Cell Number Thickness Treatment (microns² ± S.D.)(±S.D.) (microns ± S.D.) PBS^(b) 1016 ± 1397 31 ± 41 44 ± 20 S.pneumoniae ^(c) 5771 ± 2077 252 ± 140 105 ± 33  S. pneumoniae + 1486 ±1192 111 ± 119 44 ± 15 peptide^(c) p value (2-tailed)^(d) p = 0.004 p =0.020 p = 0.002 ^(a)Middle ear inflammation is assessed by measuringthree consecutive tissue sections for area of fluid in the middle ear,number of cells in the middle ear fluid, and thickness of the tympanicmembrane measured at a point away from the injection site. Datarepresent the mean ± SD animals with middle ear inflammation.Statistical evaluation is done using a paired t-test. ^(b)The PBStreated animals receive no bacteria or peptides. ^(c)Animals areinjected in one ear with S. pneumoniae + PBS and in the opposite earwith S. pneumoniae + peptide (about 10 μM). ^(d)Statistical evaluationusing a paired t-test is done using data collected from diseased animalsinjected with bacteria and comparing peptide vs. no peptide treatment.

Example 8 Assay for Crossing the Tympanic Membrane by FITC-LabeledP13-R⁹ (SEQ ID NO: 378)

BALB/c mice were injected through the bulla by the following protocol.

Three BALB/c mice at 8-12 weeks of age were anesthetized with ketamine(100 mg/kg) and xylazine (20 mg/kg) prior to administration of bacteria.A ventral midline incision was made in the neck, and the bulla exposedafter blunt dissection. The middle ear was inoculated through the bonywall with approximately 3.5 μL of a bacterial suspension (heatinactivated S. pneumoniae 10¹⁰ CFU/ml) with a thin needle. Both theright and left ears received bacteria by bulla injection.

After 24 hours, animals received an otoscopic exam using an operatingmicroscope. Mice were anesthetized as described above, and the tympanicmembrane was inspected for the presence or absence of the followingthree criteria for acute otitis media (AOM): 1) middle ear effusionbehind the tympanic membrane; 2) change in color of the tympanicmembrane from clear to red or white (indicating inflammation and/orpurulence in the middle ear); and 3) change in position of the tympanicmembrane from neutral to bulging or retracted. Only animalsdemonstrating AOM by these criteria were used.

Four ears met the criteria for AOM. FITC labeled peptide P13-R⁹ (SEQ IDNO: 378) (10 μg/30 μl) was dropped onto the middle ear. The peptide wasallowed to absorb for 10 minutes. After 10 minutes, the external earcanal was flushed twice, and blotted to get rid of any remainingpeptide. The middle ear fluid was then aspirated with a 10 μL Hamiltonsyringe with a 30 g needle, and the fluid smeared on a slide.FITC-labeled peptide was viewed under a fluorescent scope. Thephotograph demonstrates that FITC-labeled P13-R⁹ (SEQ ID NO: 378)crosses the tympanic membrane and associates with cells in middle earfluid.

FIG. 1A illustrates bright field microscopy of cells in middle earfluid.

FIG. 1B illustrates fluorescent microscopy of FITC-labeled P13-R⁹ (SEQID NO: 378) associated with cells in middle ear fluid.

Example 9 Topical Administration of P13 (SEQ ID NO: 369) Reduced MiddleEar Inflammation and Fluid Retention

In this experiment, P13 (SEQ ID NO: 369) was administered by ear dropsto reduce inflammation and fluid retention in the pre-clinical AOMmodel. BALB/c mice (n=13) received an otoscopic exam using an operatingmicroscope to establish the clinical symptoms of AOM. Mice wereanesthetized and the tympanic membrane (TM) inspected for presence orabsence of the following 3 criteria for AOM: 1) middle ear effusionbehind the TM; 2) change in color of the TM from clear to red or white,indicating inflammation and/or purulence in the middle ear; and 3)change in position of the TM from neutral to bulging or retracted. Ananimal exhibiting any of these changes was scored positive forinflammation. All mice scored negative on pre-screen and were injectedtranstympanically with 5 μL heat inactivated S. pneumonia (10⁹ CFU/mL)in both ears. Twenty-four hours post bacterial injection, mice wereexamined by otoscopic exam and those animals meeting the inflammationcriteria described above remained in the study. Of the thirteen earsscored as positive; seven ears were treated topically with P13 (SEQ IDNO: 369) (1 μg/30 μL), and six ears treated topically with PBS (30 μL).For topical treatment, animals were lightly anesthetized and P13 (SEQ IDNO: 369) or PBS was dropped onto the external tympanic membrane. Theanimals remained sedated for 15-20 minutes. Seventy-two hours postbacterial injection, animals were sacrificed and tissue histologicallyprocessed to assess middle ear disease. Inflammation was quantified bymeasuring the area of fluid present in the middle ear and number ofcells in the measured middle ear fluid area as follows. Mice wereoverdosed on anesthetic and perfused intracardially with 1.0 mL ofsaline, followed by 20 mL of fixative (1.5% paraformaldehyde-3%glutaraldehyde in 0.1 M phosphate buffer). Middle ears were decalcified,embedded in glycol methacrylate plastic, sectioned at 5 μm, mountedserially on glass slides stained, and cover-slipped. Three consecutivesections at the level of the umbo and promontory were selected formeasures of 1) area of fluid present in the middle ear; and 2) number ofcells in middle ear fluid. Each measurement was taken on the threesequential sections per specimen. The value presented for each parameterrepresents the mean of the three sections (FIG. 2). This experimentconfirmed that ear drop administration of P13 (SEQ ID NO: 369)dramatically reduced both the cellular infiltration and residual fluidin the pre-clinical AOM model. Of interest, the one animal in the P13(SEQ ID NO: 369) treatment group showing high cell number and high fluidarea is the same animal.

Example 10 Topical Administration of P13 (SEQ ID NO: 369) SignificantlyReduced the Severity and Longevity of Hearing Impairment

A. Topical Administration of P13 (SEQ ID NO: 369) Demonstrated Efficacyin a Mouse Model of AOM.

Patients with AOM frequently experience residual middle ear fluidretention which can lead to impaired hearing, recurrent infections, andin extreme conditions the need for surgical placement of ear tubes. Todetermine whether topical administration of P13 (SEQ ID NO: 369) wouldimpact hearing in a pre-clinical model of AOM, BALB/c mice (n=8), 13weeks of age, received a baseline auditory brainstem response (ABR) andotoscopic exam in both ears. ABR stimuli consisted of 20 tone-bursttrains at 4 kHz, 8 kHz, 16 kHz and 32 kHz at five intensity levels in 10dB steps. Each tone-burst had a two-ms duration, with tone burst onsetsseparated by 12 ms. Two separate trains offset by 5 dB were presented asstimuli, then combined in data analysis to determine threshold in 5 dBsteps. Responses to 300 stimulus repetitions were averaged using adigital oscilloscope. Thresholds were based on the lowest intensity atwhich a response could be identified. The number of waves present atthreshold varied somewhat, but the presence of at least two waves wasconsidered a valid threshold. An otoscopic exam was performed using anoperating microscope to establish the clinical symptoms of AOM, aspreviously described. All 8 animals remained in the study and wereinjected transtympanically with 5 μL heat inactivated S. pneumonia (10⁹CFU/mL) in both ears. Twenty-four hours post bacterial injection, micewere examined by otoscopic exam and those animals meeting theinflammation criteria remained in this study. After 24 hours, eachanimal was treated topically with P13 (SEQ ID NO: 369) (1 μg/30 μL) inone ear, and PBS (30 uL) in the other. For topical treatment, animalswere lightly anesthetized and P13 (SEQ ID NO: 369) or PBS dropped ontothe external tympanic membrane. The animals remained sedated for 15-20minutes.

Five and 13 days after bacterial injection, all animals received ABRtesting as described above. ABR data was calculated by subtracting thebaseline ABR from the post-bacterial ABR for each frequency, and thensumming all 4 frequencies (4, 8, 16 and 32 kHz). A two-way repeatedmeasure ANOVA was done for data analysis using days 5 and 13. Thisexperiment confirmed that ear drop administration of P13 (SEQ ID NO:369) significantly limited the hearing impairment seen in controltreated animals. Treatment with P13 (SEQ ID NO: 369) reduced theseverity of hearing impairment and reduced the time to resolution tonormal baseline hearing levels (FIG. 3A). P13 (SEQ ID NO: 369) treatmentdramatically reduced the number of animals with hearing loss as comparedto PBS treatment (FIG. 3B). In summary, these data confirmed theefficacy of P13 (SEQ ID NO: 369) in reducing the severity and longevityof hearing impairment.

B. Topical Administration of P13 (SEQ ID NO: 369) Demonstrated Efficacyin a Mouse Model of Chronic Otitis Media.

Eight C3H/HeJ mice (12 months of age) were given a clinical earexamination. Those animals demonstrating middle ear inflammation (6mice) were given two baseline ABRs, one week apart, and then each earwas treated topically with either PBS, or 1 μg P13 (SEQ ID NO: 369). Oneand two weeks after P13 (SEQ ID NO: 369)/PBS treatment, animals againreceived an otoscopic exam and an ABR assessment. ABR data werecalculated by subtracting the baseline ABR from the post-treatment ABRfor each frequency, and then summing all 4 frequencies. Topical P13 (SEQID NO: 369) treatment resulted in a statistically significantimprovement in hearing thresholds as assessed by ABR measurements acrossall four frequencies at both weeks 1 and 2 post-treatment. This datashowed a dramatic improvement in hearing thresholds at both time-points,with an approximate 40 db improvement at week 2. An examination of asingle frequency (4 kHz) demonstrated the impact of P13 (SEQ ID NO: 369)treatment on hearing, where at week 2 post-treatment, there was anapproximate 12 db hearing improvement in P13 (SEQ ID NO: 369) treatedanimals as compared to controls. No change was observed in the middleear inflammatory status as assessed by otoscopic exam after peptidetreatment at either time point.

C. Comparison of the D- and L-Isomer Forms of P13 (SEQ ID NO: 369) inTreating COM.

The biological half-life of peptides can be improved by using theD-isomer of amino acid residues in place of the L-isomer form. Astereoisomer of P13 (SEQ ID NO: 369) containing all D-amino acidresidues (D-P13) was therefore tested for efficacy in treating C3H/HeJmice with COM, and the results were compared to those obtained with thestereoisomer containing all L-amino acid residues (L-P13). The D-P13peptide was produced by standard methods and was purified to >95%. ThreeC3H/HeJ mice with COM were treated topically with D-P13 in both ears asdescribed above and ABRs assessed at weeks 1 and 2 post-treatment.Similar to what was seen with L-P13 treatment, treatment with D-P13 alsodemonstrated efficacy in improving hearing thresholds in COM mice withclinically documented disease. At week 2 post-treatment, D-P13 improvedhearing thresholds across all frequencies approximately 20 db ascompared to an approximate 40 db improvement after treatment with L-P13.While the L-isomer of P13 (SEQ ID NO: 369) showed a more pronouncedimprovement of hearing thresholds, the D- and L-isomer forms of P13 (SEQID NO: 369) exhibited similar levels of statistical confidence in thisexperiment.

Example 11 Topical Administration of P13 (SEQ ID NO: 369) LackedOtotoxicity

P13 (SEQ ID NO: 369) was investigated for possible negative impact onhearing in normal mice upon administration by ear drops. BALB/c mice, 16weeks of age, (n=16) received two baseline auditory brainstem response(ABR) tests one week apart, and an otoscopic exam in both ears. ABRstimuli consisted of 20 tone-burst trains at 4 kHz, 8 kHz, 16 kHz and 32kHz at five intensity levels in 10 dB steps, as previously described. Anotoscopic exam was performed using an operating microscope to establishthe clinical symptoms of AOM, as previously described. Any animal withan abnormal ABR or exam on pre-screen was not entered into the study.

All 16 animals remained in the study and were divided into five groupsas follows:

group 1: (n=6 ears) 1 μg P13 (SEQ ID NO: 369)/30 μL, topically, givenonce;

group 2: (n=7 ears) 10 μg P13 (SEQ ID NO: 369)/30 μL, topically, givenonce;

group 3: (n=7 ears) 10 μg P13 (SEQ ID NO: 369)/30 μL, topically, giventwice, 24 hours apart;

group 4: (n=6 ears) 60 μg P13 (SEQ ID NO: 369)/30 μL, topically, givenonce; and

group 5: (n=6 ears) untreated mice.

ABRs were performed at one, two, three and four weeks post P13 (SEQ IDNO: 369) treatment. The two baseline ABRs were averaged and compared tothe ABRs post P13 (SEQ ID NO: 369) treatment. This experimentdemonstrated that topical administration of P13 (SEQ ID NO: 369) did notnegatively impact hearing thresholds in these normal mice.

Example 12 Evaluation of TNF-α Secretion in Mice Treated with Peptides

The effect of several peptides on TNF-α secretion in mice in response tostimulation by CpG-ODN and LPS is studied. Peptide compositions areprepared for each peptide-R⁹, at 3 concentrations, 37 μM, 22.2 μM, and11.1 μM, and tested. Peptides demonstrating activity in this assay arefurther formulated into peptide compositions at 11.1 μM, 7.4 μM, and 3.7μM for re-assay.

BALB/c (Bagg albino) mice, about 8-12 weeks of age, are anesthetizedwith a subcutaneous injection of xylazine & ketamine (about 0.1 mg/30 gmbody weight). The mice are injected in both ears with either 1.25 ug/mlCpG-ODN or 1 ng/ml LPS. Twenty-four hours later the mice are treatedtopically (ear drop) with 1 μg peptide/30 μl in one ear and PBS (30 μl)in the other. Twenty-four hours post peptide/PBS treatment, middle earfluid is collected and analyzed for TNF-α secretion by ELISA. Earsexhibiting lesser TNF-α secretion than the control ears identifypeptides that effectively inhibit TNF-α secretion in the live mouse.

Example 13 Effects of Peptides on Mice with Noise-Induced Hearing Loss

Mice (CBA/CaJ) received baseline Auditory Brainstem Response (ABR)testing followed by treatment and noise exposure. ABR testing was done:immediately following; 24 hours; 48 hours; one week; and two weeks,following noise exposure. Peptide and control peptide (1 μg) wereadministered topically by drops placed on the tympanic membrane.

Four treatment groups were used: A) peptide/control treatment both pre-and post-noise exposure; B) peptide/control treatment pre-noiseexposure; C) peptide/control treatment post-noise exposure; and D)peptide/control treatment multiple dosing post-noise exposure.

Hearing Thresholds:

ABR audiometry to pure tones was used to evaluate cochlear function.Mice were anesthetized and the individual ears of each mouse werestimulated with a closed tube sound delivery system sealed into the earcanal. The ABR to tone-burst stimuli at 4, 8, 16, and 32 kHz wererecorded and thresholds obtained for each ear.

Peptide Treatment:

Animals were lightly anesthetized and peptide or control dropped ontothe external tympanic membrane. The animals remained sedated for 15-20minutes.

Noise Exposure:

Mice were exposed to broad band noise at 100 dB(A) SPL for 2 hrs/day.ABRs were performed immediately post-noise exposure and hearingthresholds quantified at both 16 and 32 kHz and subtracted frompre-noise exposure ABR thresholds.

Results:

Ears treated with P13 (SEQ ID NO: 369) suffered substantially-lesshearing loss than did ears treated with the control peptide, asillustrated in FIG. 5.

Example 14 P13 (SEQ ID NO: 369) and P7 (SEQ ID NO: 379) InhibitTNF-α-Stimulated by Danger Signals from Necrotic Cell Extracts

Acoustical trauma can cause necrotic cell death, which is associatedwith the release of danger signals that can stimulate the immune systemthrough toll-like receptors. The inflammatory response can contributesubstantially to the damage from the initial injury and exacerbatenoise-induced hearing loss.

P13 (SEQ ID NO: 369) and P7 (SEQ ID NO: 379) demonstrated in vitroinhibition of TNF-α when cells were stimulated with NCE. NCE wasprepared from RAW 264.7 cells by multiple freeze/thaws. A fresh colonyof RAW264.7 cells was incubated with P13 (SEQ ID NO: 369), P7 (SEQ IDNO: 379), or a control peptide (30 μg/mL) for 15 minutes and thenstimulated with NCE. After 4 hours, supernatants were collected andassayed for TNF-α by ELISA. Multiple experiments were performed, and theTNF-α production in cells incubated with peptide was compared to cellswithout peptide, as illustrated in FIG. 6. Both P13 (SEQ ID NO: 369) andP7 (SEQ ID NO: 379) significantly inhibited NCE-stimulated TNF-αproduction as compared to the control peptide. As a control, the NCE wasalso examined alone (no cells) for TNF-α content, which was negligible(data not shown).

The abilities of P13 (SEQ ID NO: 369) and P7 (SEQ ID NO: 379) to inhibitNCE-stimulated TNF-α production indicated that P13 (SEQ ID NO: 369) andP7 (SEQ ID NO: 379) can suppress TLR-induced inflammation in necrotictissue, such as noise-damaged tissue associated with noise-inducedhearing loss.

Example 15 Topical Administration of P13 (SEQ ID NO: 369) Delays Onsetof Age-Related Hearing Loss

C57Bl/6 mice develop age-related hearing loss. The progressive hearingloss begins at about 1 to 2 months with a loss in the highest spectralfrequencies, which increases in severity and spreads to lowerfrequencies over the next 12 to 15 months. The induction of aBak-dependent mitochondrial apoptosis program in response to oxidativestress is a mechanism of age-related hearing loss in these mice.

C57Bl/6 mice (n=10) received baseline ABRs at 12 weeks and were treatedwith P13 (SEQ ID NO: 369) in one ear while the contralateral earremained untreated. P13 (SEQ ID NO: 369) delayed hearing loss in allfour frequencies tested in 50% (n=5) of the mice. The 5 mice withpositive effects are represented in FIG. 7 to demonstrate the magnitudeand timing of hearing loss delay. Hearing thresholds at 32, 16, 8 and 4kHz are shown. Treatment schedule for P13 (SEQ ID NO: 369), administeredtopically as ear drops, is shown in FIG. 7 a, with hash marks indicatingincidents of administration.

Example 16 P13 (SEQ ID NO: 369) Improves Hearing Levels in Normal BALB/cMice

In a six-week study, normal BALB/c mice were treated topically (eardrops) with 1 μg P13 (SEQ ID NO: 369) at weeks 0 and 5. Hearingthresholds were quantified by ABRs at 4, 8, 16, and 32 kHz over a sixweek period. Hearing improvement was calculated by subtractingpost-treatment ABR from the background ABR and summing acrossfrequencies. The results are illustrated in FIG. 8.

Administration of P13 (SEQ ID NO: 369) to an ear resulted in rapidimprovement in hearing, which was sustained for about two to about threeweeks, whereupon the hearing quality returned to the native level.Re-administration of P13 (SEQ ID NO: 369) to the same ear resulted inhearing improvement similar to what had been observed upon initialadministration.

EMBODIMENTS

The following non-limiting embodiments provide representative examplesof the invention, but do not limit the scope of the invention.

The following Embodiments describe methods of treating noise-inducedhearing loss.

Embodiment 1

A method of treating noise-induced hearing loss, the method comprisingadministering a therapeutically-effective amount of a peptide of Formula(I) or Formula (II) to a subject in need or want thereof,(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

Embodiment 2

The method of Embodiment 1, wherein the peptide is a peptide of Formula(I).

Embodiment 3

The method of any one of Embodiments 1 and 2,

wherein X¹ is A, D, E, K or is absent; X⁴ is A, E, H, I, K, R, or Y; X⁸is A, F, P, S, T, W, or Y; and X⁹ is A, D, E, or K.

Embodiment 4

The method of any one of Embodiments 1-3, wherein cap^(N) is H andcap^(C) is OH.

Embodiment 5

The method of any one of Embodiments 1-4, wherein at least one aminoacid residue of the peptide possesses the D-configuration.

Embodiment 6

The method of any one of Embodiments 1-5, wherein at least one of aminoacid residues X¹⁻¹¹ possesses the D-configuration.

Embodiment 7

The method of any one of Embodiments 1-6, wherein pep^(N), pep^(C), andtran^(N) are absent, and tran^(C) is a transducing sequence.

Embodiment 8

The method of any one of Embodiments 1-7, wherein the transducingsequence is a poly-arginine sequence.

Embodiment 9

The method of Embodiment 8, wherein the poly-arginine sequence consistsof about nine arginine residues.

Embodiment 10

The method of any one of Embodiments 8 and 9, wherein at least onearginine residue of the poly-arginine sequence possesses theD-configuration.

Embodiment 11

The method of any one of Embodiments 8-10, wherein each residue of thepoly-arginine sequence possesses the D-configuration.

Embodiment 12

The method of any one of Embodiments 1-11, wherein the peptide isadministered orally, topically, intraaurally, parenterally,intravenously, intra-arterially, subcutaneously, intramuscularly,intracranially, or intranasally.

Embodiment 13

The method of any one of Embodiments 1-12, wherein the peptide isadministered topically.

Embodiment 14

The method of any one of Embodiments 1-13, wherein the peptide isadministered to the skin, hair, outer ear, tympanic membrane, buccalcavity, nasal cavity, or sublingual cavity.

Embodiment 15

The method of any one of Embodiments 1-14, wherein the peptide isadministered to the tympanic membrane.

Embodiment 16

The method of any one of Embodiments 1-15, wherein the peptide isadministered in the form of a drop.

Embodiment 17

The method of any one of Embodiments 1-17, wherein the subject is ahuman.

Embodiment 18

The method of any one of Embodiments 1-18, wherein the peptide is apeptide of any one of SEQ ID NOS: 131-175; 177-186; 317-361; and363-368.

Embodiment 19

A method of treating noise-induced hearing loss, the method comprisingadministering a therapeutically-effective amount of a peptide to asubject in need or want thereof, wherein the peptide comprises: IGLCA(SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI(SEQ ID NO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); orEEYFM (SEQ ID NO: 305), wherein each terminus and each amino acidresidue side chain of the peptide is independently optionally cappedwith a capping group, or a stereoisomer or pharmaceutically-acceptablesalt of any of the foregoing, wherein the peptide is not SEQ ID NO: 379or SEQ ID NO: 380.

Embodiment 20

The method of Embodiment 19, wherein the peptide comprises: IGLCA (SEQID NO: 207).

Embodiment 21

The method of Embodiment 19, wherein the peptide comprises: YIKVQ (SEQID NO: 227).

Embodiment 22

The method of Embodiment 19, wherein the peptide comprises: LFNEI (SEQID NO: 252).

Embodiment 23

The method of Embodiment 19, wherein the peptide comprises: EMFTI (SEQID NO: 276).

Embodiment 24

The method of Embodiment 19, wherein the peptide comprises: YRGLL (SEQID NO: 287).

Embodiment 25

The method of Embodiment 19, wherein the peptide comprises: RIKYG (SEQID NO: 304).

Embodiment 26

The method of Embodiment 19, wherein the peptide comprises: EEYFM (SEQID NO: 305).

Embodiment 27

The method of any one of Embodiments 19-26, wherein the peptide furthercomprises a transducing sequence.

Embodiment 28

The method of Embodiment 27, wherein the transducing sequence ispositioned at the C-terminus of the peptide.

Embodiment 29

The method of any one of Embodiments 27 and 28, wherein the transducingsequence is a poly-arginine sequence.

Embodiment 30

The method of Embodiment 29, wherein the poly-arginine sequence consistsof about nine arginine residues.

Embodiment 31

The method of any one of Embodiments 19-30, wherein at least one aminoacid residue of the peptide possesses the D-configuration.

Embodiment 32

The method of any one of Embodiments 29 and 30, wherein at least onearginine residue of the poly-arginine sequence possesses theD-configuration.

Embodiment 33

The method of any one of Embodiments 29, 30, and 32, wherein eachresidue of the poly-arginine sequence possesses the D-configuration.

Embodiment 34

The method of any one of Embodiments 19-33, wherein the peptide isadministered orally, topically, intraaurally, parenterally,intravenously, intra-arterially, subcutaneously, intramuscularly,intracranially, or intranasally.

Embodiment 35

The method of any one of Embodiments 19-34, wherein the peptide isadministered topically.

Embodiment 36

The method of any one of Embodiments 19-35, wherein the peptide isadministered to the skin, hair, outer ear, tympanic membrane, buccalcavity, nasal cavity, or sublingual cavity.

Embodiment 37

The method of any one of Embodiments 19-36, wherein the peptide isadministered to the tympanic membrane.

Embodiment 38

The method of any one of Embodiments 19-37, wherein the peptide isadministered in the form of a drop.

Embodiment 39

The method of any one of Embodiments 19-38, wherein the subject is ahuman.

Embodiment 40

The method of any one of Embodiments 19-39, wherein the peptide is apeptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396.

The following Embodiments describe methods of treating age-relatedhearing loss.

Embodiment 1

A method of treating age-related hearing loss, the method comprisingadministering a therapeutically-effective amount of a peptide of Formula(I) or Formula (II) to a subject in need or want thereof,(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

Embodiment 2

The method of Embodiment 1, wherein the peptide is a peptide of Formula(I).

Embodiment 3

The method of any one of Embodiments 1 and 2, wherein X¹ is A, D, E, Kor is absent; X⁴ is A, E, H, I, K, R, or Y; X⁸ is A, F, P, S, T, W, orY; and X⁹ is A, D, E, or K.

Embodiment 4

The method of any one of Embodiments 1-3, wherein cap^(N) is H andcap^(C) is OH.

Embodiment 5

The method of any one of Embodiments 1-4, wherein at least one aminoacid residue of the peptide possesses the D-configuration.

Embodiment 6

The method of any one of Embodiments 1-5, wherein at least one of aminoacid residues X¹⁻¹¹ possesses the D-configuration.

Embodiment 7

The method of any one of Embodiments 1-6, wherein pep^(N), pep^(C), andtran^(N) are absent, and tran^(C) is a transducing sequence.

Embodiment 8

The method of any one of Embodiments 1-7, wherein the transducingsequence is a poly-arginine sequence.

Embodiment 9

The method of Embodiment 8, wherein the poly-arginine sequence consistsof about nine arginine residues.

Embodiment 10

The method of any one of Embodiments 8 and 9, wherein at least onearginine residue of the poly-arginine sequence possesses theD-configuration.

Embodiment 11

The method of any one of Embodiments 8-10, wherein each residue of thepoly-arginine sequence possesses the D-configuration.

Embodiment 12

The method of any one of Embodiments 1-11, wherein the peptide isadministered orally, topically, intraaurally, parenterally,intravenously, intra-arterially, subcutaneously, intramuscularly,intracranially, or intranasally.

Embodiment 13

The method of any one of Embodiments 1-12, wherein the peptide isadministered topically.

Embodiment 14

The method of any one of Embodiments 1-13, wherein the peptide isadministered to the skin, hair, outer ear, tympanic membrane, buccalcavity, nasal cavity, or sublingual cavity.

Embodiment 15

The method of any one of Embodiments 1-14, wherein the peptide isadministered to the tympanic membrane.

Embodiment 16

The method of any one of Embodiments 1-15, wherein the peptide isadministered in the form of a drop.

Embodiment 17

The method of any one of Embodiments 1-17, wherein the subject is ahuman.

Embodiment 18

The method of any one of Embodiments 1-18, wherein the peptide is apeptide of any one of SEQ ID NOS: 131-175; 177-186; 317-361; and363-368.

Embodiment 19

A method of treating age-related hearing loss, the method comprisingadministering a therapeutically-effective amount of a peptide to asubject in need or want thereof, wherein the peptide comprises: IGLCA(SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI(SEQ ID NO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); orEEYFM (SEQ ID NO: 305), wherein each terminus and each amino acidresidue side chain of the peptide is independently optionally cappedwith a capping group, or a stereoisomer or pharmaceutically-acceptablesalt of any of the foregoing, wherein the peptide is not SEQ ID NO: 379or SEQ ID NO: 380.

Embodiment 20

The method of Embodiment 19, wherein the peptide comprises: IGLCA (SEQID NO: 207).

Embodiment 21

The method of Embodiment 19, wherein the peptide comprises: YIKVQ (SEQID NO: 227).

Embodiment 22

The method of Embodiment 19, wherein the peptide comprises: LFNEI (SEQID NO: 252).

Embodiment 23

The method of Embodiment 19, wherein the peptide comprises: EMFTI (SEQID NO: 276).

Embodiment 24

The method of Embodiment 19, wherein the peptide comprises: YRGLL (SEQID NO: 287).

Embodiment 25

The method of Embodiment 19, wherein the peptide comprises: RIKYG (SEQID NO: 304).

Embodiment 26

The method of Embodiment 19, wherein the peptide comprises: EEYFM (SEQID NO: 305).

Embodiment 27

The method of any one of Embodiments 19-26, wherein the peptide furthercomprises a transducing sequence.

Embodiment 28

The method of Embodiment 27, wherein the transducing sequence ispositioned at the C-terminus of the peptide.

Embodiment 29

The method of any one of Embodiments 27 and 28, wherein the transducingsequence is a poly-arginine sequence.

Embodiment 30

The method of Embodiment 29, wherein the poly-arginine sequence consistsof about nine arginine residues.

Embodiment 31

The method of any one of Embodiments 19-30, wherein at least one aminoacid residue of the peptide possesses the D-configuration.

Embodiment 32

The method of any one of Embodiments 29 and 30, wherein at least onearginine residue of the poly-arginine sequence possesses theD-configuration.

Embodiment 33

The method of any one of Embodiments 29, 30, and 32, wherein eachresidue of the poly-arginine sequence possesses the D-configuration.

Embodiment 34

The method of any one of Embodiments 19-33, wherein the peptide isadministered orally, topically, intraaurally, parenterally,intravenously, intra-arterially, subcutaneously, intramuscularly,intracranially, or intranasally.

Embodiment 35

The method of any one of Embodiments 19-34, wherein the peptide isadministered topically.

Embodiment 36

The method of any one of Embodiments 19-35, wherein the peptide isadministered to the skin, hair, outer ear, tympanic membrane, buccalcavity, nasal cavity, or sublingual cavity.

Embodiment 37

The method of any one of Embodiments 19-36, wherein the peptide isadministered to the tympanic membrane.

Embodiment 38

The method of any one of Embodiments 19-37, wherein the peptide isadministered in the form of a drop.

Embodiment 39

The method of any one of Embodiments 19-38, wherein the subject is ahuman.

Embodiment 40

The method of any one of Embodiments 19-39, wherein the peptide is apeptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396.

The following Embodiments describe methods of improving hearing.

Embodiment 1

A method of improving hearing, the method comprising administering atherapeutically-effective amount of a peptide of Formula (I) or Formula(II) to a subject in need or want thereof,(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

Embodiment 2

The method of Embodiment 1, wherein the peptide is a peptide of Formula(I).

Embodiment 3

The method of any one of Embodiments 1 and 2, wherein X¹ is A, D, E, Kor is absent; X⁴ is A, E, H, I, K, R, or Y; X⁸ is A, F, P, S, T, W, orY; and X⁹ is A, D, E, or K.

Embodiment 4

The method of any one of Embodiments 1-3, wherein cap^(N) is H andcap^(C) is OH.

Embodiment 5

The method of any one of Embodiments 1-4, wherein at least one aminoacid residue of the peptide possesses the D-configuration.

Embodiment 6

The method of any one of Embodiments 1-5, wherein at least one of aminoacid residues X¹⁻¹¹ possesses the D-configuration.

Embodiment 7

The method of any one of Embodiments 1-6, wherein pep^(N), pep^(C), andtran^(N) are absent, and tran^(C) is a transducing sequence.

Embodiment 8

The method of any one of Embodiments 1-7, wherein the transducingsequence is a poly-arginine sequence.

Embodiment 9

The method of Embodiment 8, wherein the poly-arginine sequence consistsof about nine arginine residues.

Embodiment 10

The method of any one of Embodiments 8 and 9, wherein at least onearginine residue of the poly-arginine sequence possesses theD-configuration.

Embodiment 11

The method of any one of Embodiments 8-10, wherein each residue of thepoly-arginine sequence possesses the D-configuration.

Embodiment 12

The method of any one of Embodiments 1-11, wherein the peptide isadministered orally, topically, intraaurally, parenterally,intravenously, intra-arterially, subcutaneously, intramuscularly,intracranially, or intranasally.

Embodiment 13

The method of any one of Embodiments 1-12, wherein the peptide isadministered topically.

Embodiment 14

The method of any one of Embodiments 1-13, wherein the peptide isadministered to the skin, hair, outer ear, tympanic membrane, buccalcavity, nasal cavity, or sublingual cavity.

Embodiment 15

The method of any one of Embodiments 1-14, wherein the peptide isadministered to the tympanic membrane.

Embodiment 16

The method of any one of Embodiments 1-15, wherein the peptide isadministered in the form of a drop.

Embodiment 17

The method of any one of Embodiments 1-17, wherein the subject is ahuman.

Embodiment 18

The method of any one of Embodiments 1-18, wherein the peptide is apeptide of any one of SEQ ID NOS: 131-175; 177-186; 317-361; and363-368.

Embodiment 19

A method of improving hearing, the method comprising administering atherapeutically-effective amount of a peptide to a subject in need orwant thereof, wherein the peptide comprises: IGLCA (SEQ ID NO: 207);YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276);YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO:305), wherein each terminus and each amino acid residue side chain ofthe peptide is independently optionally capped with a capping group, ora stereoisomer or pharmaceutically-acceptable salt of any of theforegoing, wherein the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

Embodiment 20

The method of Embodiment 19, wherein the peptide comprises: IGLCA (SEQID NO: 207).

Embodiment 21

The method of Embodiment 19, wherein the peptide comprises: YIKVQ (SEQID NO: 227).

Embodiment 22

The method of Embodiment 19, wherein the peptide comprises: LFNEI (SEQID NO: 252).

Embodiment 23

The method of Embodiment 19, wherein the peptide comprises: EMFTI (SEQID NO: 276).

Embodiment 24

The method of Embodiment 19, wherein the peptide comprises: YRGLL (SEQID NO: 287).

Embodiment 25

The method of Embodiment 19, wherein the peptide comprises: RIKYG (SEQID NO: 304).

Embodiment 26

The method of Embodiment 19, wherein the peptide comprises: EEYFM (SEQID NO: 305).

Embodiment 27

The method of any one of Embodiments 19-26, wherein the peptide furthercomprises a transducing sequence.

Embodiment 28

The method of Embodiment 27, wherein the transducing sequence ispositioned at the C-terminus of the peptide.

Embodiment 29

The method of any one of Embodiments 27 and 28, wherein the transducingsequence is a poly-arginine sequence.

Embodiment 30

The method of Embodiment 29, wherein the poly-arginine sequence consistsof about nine arginine residues.

Embodiment 31

The method of any one of Embodiments 19-30, wherein at least one aminoacid residue of the peptide possesses the D-configuration.

Embodiment 32

The method of any one of Embodiments 29 and 30, wherein at least onearginine residue of the poly-arginine sequence possesses theD-configuration.

Embodiment 33

The method of any one of Embodiments 29, 30, and 32, wherein eachresidue of the poly-arginine sequence possesses the D-configuration.

Embodiment 34

The method of any one of Embodiments 19-33, wherein the peptide isadministered orally, topically, intraaurally, parenterally,intravenously, intra-arterially, subcutaneously, intramuscularly,intracranially, or intranasally.

Embodiment 35

The method of any one of Embodiments 19-34, wherein the peptide isadministered topically.

Embodiment 36

The method of any one of Embodiments 19-35, wherein the peptide isadministered to the skin, hair, outer ear, tympanic membrane, buccalcavity, nasal cavity, or sublingual cavity.

Embodiment 37

The method of any one of Embodiments 19-36, wherein the peptide isadministered to the tympanic membrane.

Embodiment 38

The method of any one of Embodiments 19-37, wherein the peptide isadministered in the form of a drop.

Embodiment 39

The method of any one of Embodiments 19-38, wherein the subject is ahuman.

Embodiment 40

The method of any one of Embodiments 19-39, wherein the peptide is apeptide of any one of SEQ ID NOS: 1-130; 187-316; and 381-396.

The following Embodiments describe methods of the invention.

Embodiment 1

A method of treating noise-induced hearing loss, or treating age-relatedhearing loss, or improving hearing, the method comprising administeringto a subject in need or want of any of the foregoing atherapeutically-effective amount of a peptide that is: a) a peptide ofFormula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group; or b) a peptide comprising: IGLCA (SEQ IDNO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ IDNO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQID NO: 305), wherein each terminus and each amino acid residue sidechain of the peptide is independently optionally capped with a cappinggroup, and wherein the peptide optionally further comprises atransducing sequence positioned at the C-terminus of the peptide, or astereoisomer or pharmaceutically-acceptable salt of any of the foregoingpeptides.

Embodiment 2

The method of embodiment 1, wherein at least one amino acid residue ofthe peptide possesses the D-configuration.

Embodiment 3

The method of any one of embodiments 1 and 2, wherein the transducingsequence is a poly-arginine sequence.

Embodiment 4

The method of embodiment 3, wherein the poly-arginine sequence consistsof about nine arginine residues.

Embodiment 5

The method of any one of embodiments 3 and 4, wherein at least onearginine residue of the poly-arginine sequence possesses theD-configuration.

Embodiment 6

The method of any one of embodiments 3-5, wherein each residue of thepoly-arginine sequence possesses the D-configuration.

Embodiment 7

The method of any one of embodiments 1-6, wherein the peptide is apeptide of Formula (I).

Embodiment 8

The method of any one of embodiments 1-7, wherein X¹ is A, D, E, K or isabsent; X⁴ is A, E, H, I, K, R, or Y; X⁸ is A, F, P, S, T, W, or Y; andX⁹ is A, D, E, or K.

Embodiment 9

The method of any one of embodiments 1-8, wherein cap^(N) is H andcap^(C) is OH.

Embodiment 10

The method of any one of embodiments 1-9, wherein at least one of aminoacid residues X¹⁻¹¹ possesses the D-configuration.

Embodiment 11

The method of any one of embodiments 1-10, wherein pep^(N), pep^(C), andtran^(N) are absent, and tran^(C) is the transducing sequence.

Embodiment 12

The method of any one of embodiments 1-6, wherein the peptide comprises:IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252);EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304);or EEYFM (SEQ ID NO: 305), wherein the peptide further comprises thetransducing sequence, and wherein the transducing sequence is positionedat the C-terminus of the peptide.

Embodiment 13

The method of any one of embodiments 1-6, wherein the peptide is apeptide of any one of SEQ ID NOS: 1-175; 177-361; 363-369; and 378-396.

Embodiment 14

The method of any one of embodiments 1-6, wherein the peptide is apeptide of any one of: SEQ ID NOS: 369; 378; 379; and 380.

Embodiment 15

The method of any one of embodiments 1-14, wherein the peptide isadministered orally, topically, intraaurally, parenterally,intravenously, intra-arterially, subcutaneously, intramuscularly,intracranially, or intranasally.

Embodiment 16

The method of any one of embodiments 1-15, wherein the peptide isadministered topically.

Embodiment 17

The method of any one of embodiments 1-16, wherein the peptide isadministered to the skin, hair, outer ear, tympanic membrane, buccalcavity, nasal cavity, or sublingual cavity.

Embodiment 18

The method of any one of embodiments 1-17, wherein the peptide isadministered to the tympanic membrane.

Embodiment 19

The method of any one of embodiments 1-18, wherein the peptide isadministered in the form of a drop.

Embodiment 20

The method of any one of embodiments 1-19, wherein the subject is ahuman.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the compound is a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the compound is a peptide comprising: IGLCA (SEQ ID NO:207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO:276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ IDNO: 305), wherein each terminus and each amino acid residue side chainof the peptide is independently optionally capped with a capping group,or a stereoisomer or pharmaceutically-acceptable salt of any of theforegoing, wherein the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the compound is a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the compound is a peptide comprising: IGLCA (SEQ ID NO:207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO:276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ IDNO: 305), wherein each terminus and each amino acid residue side chainof the peptide is independently optionally capped with a capping group,or a stereoisomer or pharmaceutically-acceptable salt of any of theforegoing, wherein the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the improvement of hearing, wherein thecompound is a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the improvement of normal hearing,wherein the compound is a peptide comprising: IGLCA (SEQ ID NO: 207);YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276);YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO:305), wherein each terminus and each amino acid residue side chain ofthe peptide is independently optionally capped with a capping group, ora stereoisomer or pharmaceutically-acceptable salt of any of theforegoing, wherein the peptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a compound for use in thetreatment of noise-induced hearing loss, wherein the compound is apeptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a compound for use in thetreatment of noise-induced hearing loss, wherein the compound is apeptide comprising: IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227);LFNEI (SEQ ID NO: 252); EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287);RIKYG (SEQ ID NO: 304); or EEYFM (SEQ ID NO: 305), wherein each terminusand each amino acid residue side chain of the peptide is independentlyoptionally capped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing, wherein thepeptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a compound for use in thetreatment of age-related hearing loss, wherein the compound is a peptideof Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a compound for use in thetreatment of age-related hearing loss, wherein the compound is a peptidecomprising: IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQID NO: 252); EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQID NO: 304); or EEYFM (SEQ ID NO: 305), wherein each terminus and eachamino acid residue side chain of the peptide is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing, wherein thepeptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a compound for use in theimprovement of normal hearing, wherein the compound is a peptide ofFormula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein the peptide is not SEQID NO: 369 or SEQ ID NO: 378.

In some embodiments, the invention provides a compound for use in theimprovement of normal hearing, wherein the compound is a peptidecomprising: IGLCA (SEQ ID NO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQID NO: 252); EMFTI (SEQ ID NO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQID NO: 304); or EEYFM (SEQ ID NO: 305), wherein each terminus and eachamino acid residue side chain of the peptide is independently optionallycapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing, wherein thepeptide is not SEQ ID NO: 379 or SEQ ID NO: 380.

In some embodiments, the invention provides a method of treatingnoise-induced hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of any one of SEQ ID NOS:369 and 378-380, or a pharmaceutically-acceptable salt thereof, to asubject in need or want thereof.

In some embodiments, the invention provides a method of treatingage-related hearing loss, the method comprising administering atherapeutically-effective amount of a peptide of any one of SEQ ID NOS:369 and 378-380, or a pharmaceutically-acceptable salt thereof, to asubject in need or want thereof.

In some embodiments, the invention provides a method of improvinghearing, the method comprising administering a therapeutically-effectiveamount of a peptide of any one of SEQ ID NOS: 369 and 378-380, or apharmaceutically-acceptable salt thereof, to a subject in need or wantthereof.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of noise-induced hearingloss, wherein the compound is a peptide of any one of SEQ ID NOS: 369and 378-380, or a pharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of age-related hearingloss, wherein the compound is a peptide of any one of SEQ ID NOS: 369and 378-380, or a pharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the improvement of hearing, wherein thecompound is a peptide of any one of SEQ ID NOS: 369 and 378-380, or apharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a compound for use in thetreatment of noise-induced hearing loss, wherein the compound is apeptide of any one of SEQ ID NOS: 369 and 378-380, or apharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a compound for use in thetreatment of age-related hearing loss, wherein the compound is a peptideof any one of SEQ ID NOS: 369 and 378-380, or apharmaceutically-acceptable salt thereof.

In some embodiments, the invention provides a compound for use in theimprovement of hearing, wherein the compound is a peptide of any one ofSEQ ID NOS: 369 and 378-380, or a pharmaceutically-acceptable saltthereof.

In some embodiments, the invention provides a use of a compound in thepreparation of a medicament for the treatment of noise-induced hearingloss, or treating age-related hearing loss, or improving hearing,wherein the compound is a peptide that is: a) a peptide of Formula (I)or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group; or b) a peptide comprising: IGLCA (SEQ IDNO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ IDNO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQID NO: 305), wherein each terminus and each amino acid residue sidechain of the peptide is independently optionally capped with a cappinggroup, and wherein the peptide optionally further comprises atransducing sequence positioned at the C-terminus of the peptide, or astereoisomer or pharmaceutically-acceptable salt of any of the foregoingpeptides.

In some embodiments, the invention provides a compound for use in thetreatment of noise-induced hearing loss, or treating age-related hearingloss, or improving hearing, wherein the compound is a peptide that is:a) a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), whereineach cap^(N) is independently H, alkyl, aryl, aralkyl, an acyl group, analkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonylgroup, or both cap^(N) groups together with N form a heterocycle;tran^(N) and tran^(C) are each independently a transducing sequence orabsent; pep^(N) and pep^(C) are each independently an amino acidsequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently optionallycapped with a capping group; or b) a peptide comprising: IGLCA (SEQ IDNO: 207); YIKVQ (SEQ ID NO: 227); LFNEI (SEQ ID NO: 252); EMFTI (SEQ IDNO: 276); YRGLL (SEQ ID NO: 287); RIKYG (SEQ ID NO: 304); or EEYFM (SEQID NO: 305), wherein each terminus and each amino acid residue sidechain of the peptide is independently optionally capped with a cappinggroup, and wherein the peptide optionally further comprises atransducing sequence positioned at the C-terminus of the peptide, or astereoisomer or pharmaceutically-acceptable salt of any of the foregoingpeptides.

REFERENCES

The following references, and those cited in the disclosure herein, arehereby incorporated by reference herein in their entirety.

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What is claimed is:
 1. A method of treating noise-induced hearing loss,the method comprising administering to a subject in need or want ofrelief thereof a therapeutically-effective amount of a peptide that is:a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein each cap^(N) is independently H, alkyl, aryl, aralkyl, anacyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or anaminocarbonyl group, or both cap^(N) groups together with N form aheterocycle; tran^(N) and tran^(C) are each independently a transducingsequence or absent; pep^(N) and pep^(C) are each independently an aminoacid sequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently uncapped orcapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing peptides,wherein the amino acid sequence of the peptide is not SEQ ID NO: 183,SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 369, or SEQID NO:
 378. 2. The method of claim 1, wherein at least one amino acidresidue of the peptide possesses the D-configuration.
 3. The method ofclaim 1, wherein the transducing sequence is a poly-arginine sequence.4. The method of claim 3, wherein the poly-arginine sequence consists ofabout nine arginine residues.
 5. The method of claim 3, wherein at leastone arginine residue of the poly-arginine sequence possesses theD-configuration.
 6. The method of claim 3, wherein each residue of thepoly-arginine sequence possesses the D-configuration.
 7. The method ofclaim 1, wherein the peptide is a peptide of Formula (I).
 8. The methodof claim 7, wherein X¹ is A, D, E, K or is absent; X⁴ is A, E, H, I, K,R, or Y; X⁸ is A, F, P, S, T, W, or Y; and X⁹ is A, D, E, or K.
 9. Themethod of claim 7, wherein cap^(N) is H and cap^(C) is OH.
 10. Themethod of claim 7, wherein at least one of amino acid residues X¹⁻¹¹possesses the D-configuration.
 11. The method of claim 7, whereinpep^(N), pep^(C), and tran^(N) are absent, and tran^(C) is thetransducing sequence.
 12. The method of claim 1, wherein the peptide isa peptide of any one of SEQ ID NOS: 131-182, 317-361, and 363-368. 13.The method of claim 1, wherein the peptide is administered orally,topically, intraaurally, parenterally, intravenously, intra-arterially,subcutaneously, intramuscularly, intracranially, or intranasally. 14.The method of claim 1, wherein the peptide is administered topically.15. The method of claim 1, wherein the peptide is administered to theskin, hair, outer ear, tympanic membrane, buccal cavity, nasal cavity,or sublingual cavity.
 16. The method of claim 1, wherein the peptide isadministered to the tympanic membrane.
 17. The method of claim 1,wherein the peptide is administered in the form of a drop.
 18. Themethod of claim 1, wherein the subject is a human.
 19. The method ofclaim 1, wherein the peptide is SEQ ID NO
 133. 20. The method of claim1, wherein the peptide is SEQ ID NO
 141. 21. The method of claim 1,wherein the peptide is SEQ ID NO
 151. 22. The method of claim 1, whereinthe peptide is SEQ ID NO
 166. 23. The method of claim 1, wherein thepeptide is SEQ ID NO
 167. 24. The method of claim 1, wherein the peptideis SEQ ID NO
 181. 25. The method of claim 1, wherein the peptide is SEQID NO
 182. 26. The method of claim 1, wherein the peptide is SEQ ID NO319.
 27. The method of claim 1, wherein the peptide is SEQ ID NO 327.28. The method of claim 1, wherein the peptide is SEQ ID NO
 337. 29. Themethod of claim 1, wherein the peptide is SEQ ID NO
 352. 30. The methodof claim 1, wherein the peptide is SEQ ID NO
 353. 31. The method ofclaim 1, wherein the peptide is SEQ ID NO
 367. 32. The method of claim1, wherein the peptide is SEQ ID NO
 368. 33. A method of treatingage-related hearing loss, the method comprising administering to asubject in need or want of relief thereof a therapeutically-effectiveamount of a peptide that is: a peptide of Formula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein each cap^(N) is independently H, alkyl, aryl, aralkyl, anacyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or anaminocarbonyl group, or both cap^(N) groups together with N form aheterocycle; tran^(N) and tran^(C) are each independently a transducingsequence or absent; pep^(N) and pep^(C) are each independently an aminoacid sequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently uncapped orcapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing peptides,wherein the amino acid sequence of the peptide is not SEQ ID NO: 183,SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 369, or SEQID NO:
 378. 34. The method of claim 33, wherein at least one amino acidresidue of the peptide possesses the D-configuration.
 35. The method ofclaim 33, wherein the transducing sequence is a poly-arginine sequence.36. The method of claim 33, wherein the poly-arginine sequence consistsof about nine arginine residues.
 37. The method of claim 33, wherein atleast one arginine residue of the poly-arginine sequence possesses theD-configuration.
 38. The method of claim 33, wherein each residue of thepoly-arginine sequence possesses the D-configuration.
 39. The method ofclaim 33, wherein the peptide is a peptide of Formula (I).
 40. Themethod of claim 39, wherein X¹ is A, D, E, K or is absent; X⁴ is A, E,H, I, K, R, or Y; X⁸ is A, F, P, S, T, W, or Y; and X⁹ is A, D, E, or K.41. The method of claim 39, wherein cap^(N) is H and cap^(C) is OH. 42.The method of claim 39, wherein at least one of amino acid residuesX¹⁻¹¹ possesses the D-configuration.
 43. The method of claim 39, whereinpep^(N), pep^(C), and tran^(N) are absent, and tran^(C) is thetransducing sequence.
 44. The method of claim 33, wherein the peptide isa peptide of any one of SEQ ID NOS: 131-182, 317-361, and 363-368. 45.The method of claim 33, wherein the peptide is administered orally,topically, intraaurally, parenterally, intravenously, intra-arterially,subcutaneously, intramuscularly, intracranially, or intranasally. 46.The method of claim 33, wherein the peptide is administered topically.47. The method of claim 33, wherein the peptide is administered to theskin, hair, outer ear, tympanic membrane, buccal cavity, nasal cavity,or sublingual cavity.
 48. The method of claim 33, wherein the peptide isadministered to the tympanic membrane.
 49. The method of claim 33,wherein the peptide is administered in the form of a drop.
 50. Themethod of claim 33, wherein the subject is a human.
 51. The method ofclaim 33, wherein the peptide is SEQ ID NO
 133. 52. The method of claim33, wherein the peptide is SEQ ID NO
 141. 53. The method of claim 33,wherein the peptide is SEQ ID NO
 151. 54. The method of claim 33,wherein the peptide is SEQ ID NO
 166. 55. The method of claim 33,wherein the peptide is SEQ ID NO
 167. 56. The method of claim 33,wherein the peptide is SEQ ID NO
 181. 57. The method of claim 33,wherein the peptide is SEQ ID NO
 182. 58. The method of claim 33,wherein the peptide is SEQ ID NO
 319. 59. The method of claim 33,wherein the peptide is SEQ ID NO
 327. 60. The method of claim 33,wherein the peptide is SEQ ID NO
 337. 61. The method of claim 33,wherein the peptide is SEQ ID NO
 352. 62. The method of claim 33,wherein the peptide is SEQ ID NO
 353. 63. The method of claim 33,wherein the peptide is SEQ ID NO
 367. 64. The method of claim 33,wherein the peptide is SEQ ID NO
 368. 65. A method of improving hearing,the method comprising administering to a subject in need or want thereofa therapeutically-effective amount of a peptide that is: a peptide ofFormula (I) or Formula (II),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(I),(cap^(N))(cap^(N))N-tran^(N)-pep^(N)-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_(x)-pep^(C)-tran^(C)-C(O)-cap^(C)  Formula(II), wherein each cap^(N) is independently H, alkyl, aryl, aralkyl, anacyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or anaminocarbonyl group, or both cap^(N) groups together with N form aheterocycle; tran^(N) and tran^(C) are each independently a transducingsequence or absent; pep^(N) and pep^(C) are each independently an aminoacid sequence or absent; X¹ is A, K, an acidic amino acid residue, or isabsent; X² is A, I, L, or V; X³ is A, D, I, L, P, or V; X⁴ is A, E, I,Y, or a basic amino acid residue; X⁵ is A, I, L, or V; X⁶ is A, G, S, T,or Y; X⁷ is A, E, I, L, or V; X⁸ is A, P, S, T, or an aromatic aminoacid residue; X⁹ is A, K, or an acidic amino acid residue; X¹⁰ is A, C,M, S, α-aminobutyric acid, or norvaline; X¹¹ is A, I, L, V, or isabsent; X¹² is G or is absent; x is 1, 2, or 3; cap^(C) is OH, alkoxy,aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle;and each amino acid residue side chain is independently uncapped orcapped with a capping group, or a stereoisomer orpharmaceutically-acceptable salt of any of the foregoing peptides,wherein the amino acid sequence of the peptide is not SEQ ID NO: 183,SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 369, or SEQID NO:
 378. 66. The method of claim 65, wherein at least one amino acidresidue of the peptide possesses the D-configuration.
 67. The method ofclaim 65, wherein the transducing sequence is a poly-arginine sequence.68. The method of claim 65, wherein the poly-arginine sequence consistsof about nine arginine residues.
 69. The method of claim 65, wherein atleast one arginine residue of the poly-arginine sequence possesses theD-configuration.
 70. The method of claim 65, wherein each residue of thepoly-arginine sequence possesses the D-configuration.
 71. The method ofclaim 65, wherein the peptide is a peptide of Formula (I).
 72. Themethod of claim 71, wherein X¹ is A, D, E, K or is absent; X⁴ is A, E,H, I, K, R, or Y; X⁸ is A, F, P, S, T, W, or Y; and X⁹ is A, D, E, or K.73. The method of claim 71, wherein cap^(N) is H and cap^(C) is OH. 74.The method of claim 71, wherein at least one of amino acid residuesX¹⁻¹¹ possesses the D-configuration.
 75. The method of claim 71, whereinpep^(N), pep^(C), and tran^(N) are absent, and tran^(C) is thetransducing sequence.
 76. The method of claim 65, wherein the peptide isa peptide of any one of SEQ ID NOS: 131-182, 317-361, and 363-368. 77.The method of claim 65, wherein the peptide is administered orally,topically, intraaurally, parenterally, intravenously, intra-arterially,subcutaneously, intramuscularly, intracranially, or intranasally. 78.The method of claim 65, wherein the peptide is administered topically.79. The method of claim 65, wherein the peptide is administered to theskin, hair, outer ear, tympanic membrane, buccal cavity, nasal cavity,or sublingual cavity.
 80. The method of claim 65, wherein the peptide isadministered to the tympanic membrane.
 81. The method of claim 65,wherein the peptide is administered in the form of a drop.
 82. Themethod of claim 65, wherein the subject is a human.
 83. The method ofclaim 65, wherein the peptide is SEQ ID NO
 133. 84. The method of claim65, wherein the peptide is SEQ ID NO
 141. 85. The method of claim 65,wherein the peptide is SEQ ID NO
 151. 86. The method of claim 65,wherein the peptide is SEQ ID NO
 166. 87. The method of claim 65,wherein the peptide is SEQ ID NO
 167. 88. The method of claim 65,wherein the peptide is SEQ ID NO
 181. 89. The method of claim 65,wherein the peptide is SEQ ID NO
 182. 90. The method of claim 65,wherein the peptide is SEQ ID NO
 319. 91. The method of claim 65,wherein the peptide is SEQ ID NO
 327. 92. The method of claim 65,wherein the peptide is SEQ ID NO
 337. 93. The method of claim 65,wherein the peptide is SEQ ID NO
 352. 94. The method of claim 65,wherein the peptide is SEQ ID NO
 353. 95. The method of claim 65,wherein the peptide is SEQ ID NO
 367. 96. The method of claim 65,wherein the peptide is SEQ ID NO
 368. 97. The method of claim 1, whereinthe peptide is administered in the form of an ointment, cream, liquid,gel, or salve.
 98. The method of claim 1, wherein the peptide isadministered in the form of an aerosol, vapor, spray, or mist.
 99. Themethod of claim 33, wherein the peptide administered is in the form ofan ointment, cream, liquid, gel, or salve.
 100. The method of claim 33,wherein the peptide administered is in the form of an aerosol, vapor,spray, or mist.
 101. The method of claim 65, wherein the peptideadministered is in the form of an ointment, cream, liquid, gel, orsalve.
 102. The method of claim 65, wherein the peptide administered isin the form of an aerosol, vapor, spray, or mist.